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AN  ANALYSIS  OF  THE  NERVOUS  CONTROL  OF  THE 
CARDIOVASCULAR  CHANGES  DURING  OCCLU- 
SION OF  THE  HEAD  ARTERIES  IN  CATS 


BY 

CORA  SENNER  WINKIN 


SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  REQUIREMENTS  FOR 

THE  DEGREE  OF  DOCTOR  OF  PHILOSOPHY,  IN  THE  FACULTY 

OF  PURE   SCIENCE,  COLUMBIA  UNIVERSITY 


REPRINTED  FROM  THE  AMERICAN  JOURNAL  OP  PHYSIOLOGY, 

Vol.  60,  No.  1,  p.  1,  March,  1922 

Baltimore,  Maryland 


BIOLOGY 
LIBRARY 

G 

Reprinted  from  THE  AMERICAN  JOURNAL  OF  PHYSIOLOGY 

Vol.  60,  No.  1,  March,  1922 


AN  ANALYSIS  OF  THE  NERVOUS  CONTROL  OF  THE  CAR- 
DIOVASCULAR CHANGES  DURING  OCCLUSION 
OF  THE  HEAD  ARTERIES  IN  CATS 

CORA  SENNER  WINKIN 

From  the  Department  of  Physiology,  Columbia  University 

Received  for  publication  November  4,  1921 

STATEMENT  OF  THE  PROBLEM.1  The  relations  dealt  with  in  this 
study  are  the  cardio-vascular  relations  found  in  the  mammalian  or- 
ganism under  extreme  conditions  of  stress.  The  procedure  of  the  ex- 
periments, occlusion  of  the  head  arteries,  gives  a  complete  anemia  of  the 
brain,  and  thus  produces  a  profound  change  in  the  internal  environment 
of  the  animal.  To  this  the  mammal  tends  to  respond  by  a  series  of 
vigorous  reactions.  These  reactions,  moreover,  seem  to  go  in  a  direc- 
tion opposite  to  that  of  the  change  in  internal  conditions  of  a  par- 
ticular group  of  cells.  Thus,  with  an  asphyxial  accumulation  of  carbon 
dioxide  in  the  medium  surrounding  the  critical  medullary  cells,  there 
is  released  an  entire  series  of  reactions  which,  could  they  all  be  carried 
to  completion,  would  reduce  the  tension  of  this  gas  in  the  body  fluids 
of  the  cerebral  region.  Prominent  among  these  reactions  is  a  great  and 
prolonged  rise  of  blood  pressure,  involving  the  extreme  resources  of  the 
organism,  tending  to  send  a  greater  volume  of  blood  to  the  anemic 
regions,  and  hence  to  decrease  the  concentration  of  the  carbon  dioxide 
in  the  nerve  cells  of  the  medulla  oblongata.  In  the  cat,  this  anemic 
rise  of  blood  pressure  can  be  well  controlled  anatomically,  and  is  suscep- 

1  A  preliminary  note  has  been  published  in  Proc.  Soc.  Exper.  Biol.  and  Med., 
1921,  xviii,  155. 

1 

THE   AMERICAN   JOURNAL   OP   PHYSIOLOGY,    VOL.    60,    NO.    1 


4787 t 6 


2  CORA   SENNER   WINKIN 

tible  of  rather  exact  registration.  Moreover,  artificial  respiration  may 
be  maintained  throughout  the  reaction,  and  thus  the  activity  of  the 
peripheral  mechanisms,  the  heart,  blood  vessels  and  internal  secretions, 
be  kept  free  from  the  central  asphyxial  changes.  Furthermore,  under 
artificial  respiration,  the  reaction  may  be  obtained  repeatedly  in  the 
same  animal.  It  has  therefore  offered  an  opportunity  for  analyzing 
the  factors  involved  in  such  an  emergency  reaction  to  inimical  condi- 
tions in  the  central  mechanism. 

Since  the  work  of  Ludwig,  Cyon  and  Bezold  in  the  sixties,  the  im- 
portance of  the  splanchnic  vasomotor  fibers  for  the  production  of 
extensive  changes  in  blood  pressure  has  been  recognized.  The  re- 
lated action  of  the  discharge  of  adrenalin  into  the  blood  stream  has 
recently  received  considerable  emphasis.  However,  the  degree  to 
which  either  the  splanchnic  constrictor  fibers  or  the  secretion  of  the 
adrenal  glands  is  involved  under  such  conditions  of  stress  as  evoke  the 
anemic  rise,  has  not  been  evaluated  with  sufficient  accuracy.  This 
study  has  therefore  been  concerned  particularly  with  the  efferent 
nervous  pathways  of  the  "anemic  rise"  of  pressure:  above  all,  with  the 
degree  to  which  it  involves  the  splanchnic  constrictor  fibers.  The 
extent  to  which  splanchnic  involvement  has  made  for  adrenal  activity 
has  then  been  investigated.  Finally,  the  influence  of  the  cardiac 
innervation,  insofar  as  this  may  directly  effect  changes  in  the  level  of 
blood  pressure  during  anemia,  has  also  been  examined. 

Through  the  restriction  of  the  effect  of  the  arterial  occlusion  to  the 
head  region  alone,  the  activation  of  the  vascular  response  by  the  medulla 
oblongata  is  under  close  experimental  control.  Accordingly,  the  cen- 
tral relations  of  the  various  nervous  levels  controlling  the  efferent 
channels  could  also  be  investigated.  Indeed,  the  analysis  of  the 
peripheral  factors  was  in  large  part  undertaken  in  order  to  establish 
more  accurately  the  functional  organization  of  the  central  nervous 
mechanism  upon  which  the  vascular  response  depends,  that  is,  the 
extent  to  which  the  peripheral  agents  executing  the  vascular  responses 
of  the  intact  animal  are  activated  either  by  the  higher  nervous  levels, 
or  by  the  spinal  cord  alone. 

This  analysis  was  undertaken  in  connection  with  the  studies  on  the 
central  nervous  system  carried  out  under  Prof.  F.  H.  Pike,  which  have 
dealt  particularly  with  the  bearing  of  its  organization  on  the  problem 
of  "spinal  shock."  In  connection  with  the  problems  here  opened  up 
it  was  necessary  to  ascertain  the  exact  nature  of  the  peripheral  and 
central  factors  controlling  the  typical  vascular  response  in  animals  in 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  3 

which  either  no  lesions  within  the  central  system  were  undertaken,  or 
when  these  were  inflicted,  no  interval  for  recovery  after  the  operation 
was  allowed.  In  comparison  with  such  data,  a  study  of  the  vascular 
responses  after  recovery  from  transection  of  the  spinal  cord  could  be 
undertaken  more  intelligently,  and  the  actual  changes  wrought  by  the 
so-called  shock  effect  evaluated  with  greater  precision. 

HISTORY  OF  THE  METHOD.  Initiated  by  the  very  early  work  on 
abdominal  ligation  of  Stenson  (1)  and  Swammerdam  (2),  Magendie 
and  Poiseuille  (3)  and  Sir  Astley  Cooper  (4)  in  the  early  nineteenth 
century  worked  out  the  procedure  of  cerebral  ligation,  particularly 
the  isolation  of  the  four  chief  arterial  channels  to  the  head,  and  noted 
the  circulatory  changes  which  followed.  Batelli  (5)  and  Hill  (6)  have 
given  the  earlier  history  of  the  procedure  in  some  detail. 

The  experiments  of  the  eighteen  fifties  and  sixties  led  to  the  recogni- 
tion of  the  nervous  organs  as  the  chief  agents  in  activating  the  changes 
following  arterial  ligation:  thus  the  work  of  Kussmaul  and  Tenner 
(7),  Brown  Sequard  (8),  (9)  and  Vulpian  (10)  on  the  head  area  and  of 
Schiffer  (11)  on  the  spinal  cord.  The  emphasis  of  the  importance  of 
the  medulla  for  the  maintenance  of  life  as  given  by  the  work  of  Le 
Gallois  and  its  extension  by  Flourens  (12)  was  still  more  increased  by 
the  localization  in  the  same  region  of  the  vasoconstrictor  center  as  soon 
accomplished  by  Ludwig  (13),  Owsjannikow  and  Dittmar,  and  soon, 
led  up  to  the  most  complete  studies  on  occlusion  of  the  head  arteries 
carried  out  by  Sigmund  Mayer  (14),  (15).  Mayer  not  only  described 
the  series  of  changes  following  anemia  with  great  detail  and  accuracy, 
but  also  recognized  that  the  elicitation  of  the  anemic  rise  was  dependent 
on  conditions  of  functional  conductivity  within  the  brain  stem.  He 
also  saw  that  occlusion  of  the  head  arteries  was  comparable  to  decapi- 
tation with  the  knife,  and  that  the  various  functions  retained  following 
cerebral  ligation  were  all  to  be  attributed  to  the  activity  of  the  spinal 
cord,  notably  the  residual  spinal  level  of  blood  pressure  of  50  to  60  mm. 

Gouty  (16)  produced  circulatory  obstruction  in  the  head  region  by  the 
injection  of  lycopodium  spores.  This  work,  contemporaneous  with 
that  of  Mayer  and  equally  detailed,  but  carried  out  under  the  influence 
of  the  earlier  work  of  Goltz  (17),  (18)  and  Vulpian,  stressed  the  residual 
spinal  functions,  maintained  following  isolation  of  the  medulla.  Sub- 
sequent work  on  cerebral  anemia  was  almost  exclusively  done  from 
this  point  of  view.  Thus  the  papers  of  Schlesinger  (20),  Kowalewsky 
and  Adamtik  (21),  Bochefontaine  and  Vulpian  (22),  Mayer  (23), 
attempted  to  combat  this  viewpoint  by  an  analysis  of  the  differential 


4  CORA   SENNER  WINKIN 

* 

effect  of  compression  of  the  abdominal  aorta.  Konow  and  Stenbeck 
(24)  and  Landergren  (25)  more  recently  stressed  the  functional  sur- 
vival of  the  cord  in  the  decapitated  animal  preparation.  The  residual 
spinal  blood  pressure  was  analyzed  by  Pike  (26)  (1912)  who  showed 
that  afferent  impulses,  presumably  from  skeletal  muscles,  were  re- 
sponsible for  it.  His  observation  that  a  further  fall  occurs  on  paralysis 
of  skeletal  muscles  by  curare  has  recently  been  confirmed  by  Langley, 
1919  (27). 

A  revival  of  interest  in  the  central  relations  of  the  asphyxial  picture, 
particularly  to  the  higher  nervous  levels,  was  in  part  achieved  through 
the  reexamination  of  the  problems  of  resuscitation  of  the  organism  by 
Stewart,  (28),  (29),  (30),  (31),  (32),  (33)  Pike  and  Guthrie.  These 
observations  threw  sharply  into  relief  the  dependence  of  resuscitation 
on  the  medullary  respiratory  and  vasoconstrictor  mechanisms  rather 
than  on  other  organs,  which,  whatever  their  importance,  were  found 
neither  as  sensitive  nor  as  susceptible  as  the  medullary  and  higher 
cells.  The  functional  activity  of  the  medulla  was  abolished  15  minutes 
or  more,  and  in  its  abeyance,  no  independent  existence  of  the  animal 
could  be  reestablished.  An  analysis  of  the  conditions  of  so-called 
spinal  shock  was  undertaken  by  Pike  (34),  (35),  (26),  who  employed 
the  procedure  of  cerebral  anemia,  and  the  vascular  response  obtainable 
from  it,  as  a  means  of  comparing  the  various  functional  levels  of  the 
central  nervous  system.  In  this  way  the  central  relations,  particularly 
to  the  bulbar  levels,  of  the  vascular  response  in  anemia  were  clearly 
indicated.  A  further  extension  of  this  problem  is  found  in  the  study 
Of  Yates  (36),  in  which  the  response  to  anemia  was  used  as  a  criterion 
of  the  degree  of  recovery  of  the  vascular  system  following  spinal  tran- 
section.  These  studies  bring  out  the  importance  of  the  maintenance 
of  medullary  activity  as  the  essential  factor  in  the  avoidance  of  a 
shock  effect  and  the  relative  incompetence  of  the  spinal  cord  in  the 
initiation  of  significant  adaptive  responses. 

Consideration  of  the  excitatory  and  depressing  effects  of  the  blood 
gases  has  led  toward  a  recognition  of  their  importance  in  influencing 
the  behavior  of  the  medullary  cells.  The  literature  of  the  subject  is 
reviewed  by  Bethe  (37),  Hill  and  Flack  (38),  Hasselbach  (39).  Pike, 
Coombs  and  Hastings  (40),  (41)  have  pointed  out  the  adaptive  nature 
of  the  nervous  changes  induced  by  a  rapid  lowering  of  CO2  tension  in 
dyspneic  blood,  and  have  suggested  that  in  thus  acting  in  a  direction 
opposite  to  environmental  change,  the  organism  meets  the  conditions 
by  adjustment  of  physical  equilibrium  as  prescribed  by  le  Chatelier's 


CARDIOVASCULAR  CHANGES  DURING  CEREBRAL  ANEMIA       5 

theorem.  Mathison  (42),  (43)  has  shown  the  very  much  greater  sensi- 
tivity of  the  medullary  over  the  spinal  cells  in  their  response  to  the 
asphyxial  agents  such  as  increased  CO2  or  lactic  acid,  or  decreased 
oxygen.  Pike  and  Scott  (44)  have  discussed  the  regulation  of  H-ion 
concentration  in  connection  with  the  regulation  of  mammalian  internal 
environment. 

METHOD.  In  the  present  study  advantage  was  taken  of  the  rever- 
sibility of  the  procedure  of  cerebral  anemia.  The  ability  to  repeat  the 
initial  stimulating  effect  of  the  insult  on  the  medullary  cells  was  ex- 
ploited, rather  than  its  abolition  of  conductivity  within  them.  The 
specific  problems  attacked  were  dealt  with  in  terms  of  the  intensity  and 
duration  of  the  anemic  rise,  under  given  central  and  peripheral  lesions. 
A  seemingly  significant  series  of  observations  on  the  changes  at  the 
periphery  could  be  obtained  by  means  of  the  pronounced  differences 
in  the  character  of  the  curves  recorded. 

Mayer  (14)  had  called  attention  to  the  fact  that  the  magnitude  of 
the  vasomotor  effect  under  asphyxia  could  be  approached  only  by  the 
effect  of  compression  of  the  thoracic  aorta,  or  injection  of  strychnine. 
From  Mathison's  work  (42),  (43),  especially  from  his  conception  that 
all  forms  of  asphyxia  are  due  to  definite  increase  of  the  acid  content 
of  the  blood,  cerebral  anemia  can  probably  be  assumed  always  to  be 
acting  at  a  maximum.  The  procedure  followed  was  essentially  that 
indicated  by  Stewart  (28).  As  here  used,  the  emphasis  lay  especially 
on  the  restriction  of  the  occlusion  time  to  as  narrow  a  limit  as  possible, 
in  order  to  insure  more  rapid  recovery.  Accordingly,  the  shortest 
possible  occlusion  period  was  uniformly  employed  and  as  a  routine 
procedure  the  head  arteries  were  released  as  soon  as  the  spontaneous 
fall  of  pressure  at  the  end  of  the  response  set  in. 

The  experiments  were  all  carried  out  on  cats.  Ether  was  the  anes- 
thetic uniformly  employed,  and  administered  by  tracheal  cannula. 
The  purpose  of  the  study  was  essentially  to  determine  the  degree  of 
involvement  of  the  chief  factors  concerned,  rather  than  their  minute 
evaluation.  This  has  been  left  for  subsequent  study.  The  extensive 
series  of  Stewart  served  as  a  basis  of  comparison  and  control. 

The  head  arteries  were  all  secured  outside  the  thoracic  wall,  the 
branches  of  the  left  subclavian,  separately  secured  in  the  axilla,  the 
right  carotid,  and  right  subclavian  from  within  the  carotid  sheath  in 
the  neck;  the  left  carotid  held  the  blood  pressure  cannula.  All  the 
arteries  were  kept  under  ligatures  ready  to  be  occluded  by  clamps  at 
the  convenience  of  the  experimenter.  Since  there  was  no  interference 


6  CORA   SENNER   WINKIN 

with  extra-pulmonic  pressure  through  the  operative  procedure,  artificial 
respiration  could  be  dispensed  with  as  long  as  the  medullary  cells 
remained  functional. 

Prior  to  occlusion,  ether  was  reduced  until  various  obvious  tests 
of  the  activity  of  the  brain  stem  could  be  secured,  the  return  of  a  vigorous 
corneal  reflex  always  being  awaited  before  the  circulatory  arrest  was 
made.  With  the  elicitation  of  the  corneal  reflex,  artificial  respiration 
was  begun,  and  the  clamps  on  the  arteries  immediately  adjusted.  Care 
is  needed  to  include  all  the  arterial  branches  isolated  in  the  clamps. 

With  the  adjustment  of  the  clamps,  the  entire  series  of  peripheral 
effects  follows;  the  eye  reflexes  are  immediately  lost,  and  within  about 
20  seconds  the  more  marked  peripheral  effects  are  released.  Deep  and 
labored  breathing  sets  in,  skeletal  convulsions  appear,  and  a  sharp  rise 
of  blood  pressure  is  recorded  which  often  reaches  200  mm.  Hg.  or  more 
(fig.  5a).  This  frequently  outlasts  the  other  functions;  the  pressure 
may  not  begin  to  fall  until  some  10  to  80  seconds  after  respiratory 
failure. 

The  time  from  the  shutting  off  of  the  arteries  to  the  circulatory 
failure  is  then  taken  as  the  complete  occlusion  time.  On  the  average, 
this  occupied  3  minutes. 

Immediately  following  reestablishment  of  the  circulation  there  is  a 
profound  depression  of  all  functions.  Blood  pressure  continues  falling 
markedly  when  the  arteries  are  released,  and  finally  reaches  a  level  of 
about  50  mm.  No  other  medullary  responses  are  elicitable  at  this  time. 
Artificial  respiration  is,  of  course,  maintained  throughout  the  period  of 
depression,  and  until  such  time  as  the  bulbar  functions  again  become 
evident. 

If  no  further  lesions  are  inflicted,  occlusions  of  3  to  4  minutes  are 
usually  followed  by  a  beginning  of  recovery  within  5  to  7  minutes  after 
release  of  the  arteries.  Blood  pressure  usually  starts  rising  first,  and 
after  a  rise  of  10  to  15  mm.  spontaneous  respiratory  gasps  reappear. 
Pressure  continues  to  rise,  respiratory  movements  become  more  and 
more  frequent;  soon  normal  pressure  is  regained  and  the  animal  breathes 
quietly  and  regularly.  Ten  to  15  minutes  after  release  of  the  arteries, 
pressure  is  usually  normal,  vibrissae  are  erect,  and  the  corneal  reflex 
is  again  elicitable.  At  this  point,  a  renewed  occlusion  of  the  head 
arteries  may  be  done  and  the  entire  cycle  repeated. 

The  modification  of  anatomical  conditions  was  usually  carried  out 
in  the  interval  of  depression  following  a  control  occlusion.  In  this 
way  further  etherization  was  avoided.  Except  under  certain  specified 


CARDIOVASCULAR   CHANGES   DURING    CEREBRAL    ANEMIA  7 

conditions,  the  various  lesions  did  not  materially  change  or  delay  the 
picture  of  the  recovery  outlined. 

THE  EXPERIMENTAL  RESULTS.  1 .  The  role  of  the  splanchnic  constric- 
tor fibers  in  the  rise  of  pressure  during  cerebral  anemia:  Following  the 
work  of  Claude  Bernard  in  1848  who  showed  that  the  section  of  the 
cervical  cord  caused  a  considerable  fall  of  blood  pressure,  Bezold,  Ludwig 
and  Cyons  (46),  (47),  (48),  (49),  (50)  measured-  the  magnitude  of  these 
changes  and  showed  their  dependence  on  the  integrity  of  the  splanchnic 
system.  There  was  thus  demonstrated  the  relation  of  the  blood  pressure 
changes  to  the  level  which  is  maintained  after  the  continuity  of  the  cord 
with  the  brain  has  been  interrupted. 

Mall  (51)  showed  that  frequently  27  per  cent  of  the  blood  in  dogs  was 
transferred  by  the  splanchnic  system,  thus  explaining  the  great  increase 
•of  volume  in  the  extremities  during  rises  of  systemic  pressure  (52). 
Edwards  (53)  calculated  that  85  cc.  of  blood  in  dogs  were  trans- 
located under  splanchnic  stimulation.  In  spite  of  its  probable  involve- 
ment in  the  powerful  vasomotor  response  of  the  anemic  rise,  very  little 
direct  evidence  for  its  participation  has  been  obtained.  Hill's  (46) 
reference  to  the  splanchnic  nerves  in  cerebral  anemia  is,  so  far  as  can 
be  ascertained,  largely  by  way  of  implication.  For  asphyxia  itself 
both  V.  Anrep  (54)  and  Cathcart  and  Clark  (55)  have  argued  for  con- 
siderable splanchnic  participation  from  the  dependence  on  the  central 
nervous  system  of  the  adrenalin  release  obtained.  Finally,  some  in- 
direct evidence  for  splanchnic  nerve  involvement  has  been  obtained  by 
section  of  the  spinal  cord  in  cerebral  occlusion.  Nawalichin  (56) 
found  that  the  vasomotor  changes  following  obstruction  of  the  cere- 
bral circulation  were  practically  obliterated  when  the  cord  had  been 
sectioned  in  the  cervical  region.  The  same  observation  was  made  by 
Stewart  (28). 

In  order  to  obtain  any  exact,  or  possibly  even  quantitative,  evalua- 
tion of  the  actual  involvement  of  the  splanchnic  system,  other  factors 
concerned  in  the  maintenance  and  change  of  blood  pressure  must  be 
isolated.  Three  factors  in  the  nervous  regulation  must  above  all  be 
properly  controlled.  These  are  (a),  the  indirect  effect  of  the  activity 
of  the  skeletal  muscles;  (&),  the  influence  of  the  cardiac  innervation;  and 
(c),  the  non-splanchnic  constrictor  (or  possibly  dilator)  fibers  in  the 
vasomotor  system. 

a.  The  influence  of  the  skeletal  muscles  in  the  anemic  rise.  The 
older  authors,  Mayer  and  Gouty,  used  curarized  animals,  rabbits  and 
dogs,  for  their  experiments  on  cerebral  occlusions,  and  reported  anemic 


8  CORA    SENNER   WINKIN 

rises  as  great  in  magnitude  and  duration  as  those  recorded  by  Stewart 
(28)  or  those  herein  obtained.  The  relative  volume  of  blood  held  in 
these  animals  within  the  splanchnic  system,  as  compared  with  that 
controlled  by  the  somatic  innervation  is,  however,  somewhat  different 
from  that  in  cats.  Little  experimental  attention  was  here  given  to 
this  problem.  In  one  animal,  however,  curare  was  injected  and  a  vigor- 
ous anemic  response  was  obtained.  The  occlusion  time  was  normal  (3 
minutes) ;  the  anemic  increment,  however,  was  below  the  average,  being 
only  80  mm.  In  another  cat,  both  sciatics  and  the  brachial  plexuses 
on  both  sides  were  divided.  Pressure  did  not  fall  after  the  lesions. 
Both  stellate  ganglia  were  then  removed.  The  animal  gave  an  anemic 
increment  of  100  mm.  Hg. 

It  seems  accordingly  that  the  muscular  factor  is  of  no  primary  signifi- 
cance in  either  the  initiation  or  the  maintenance  of  the  anemic  rise. 
The  fact  that  no  great  depression  of  the  level  of  blood  pressure  results 
in  spite  of  extensive  elimination  of  muscular  innervation  is  interesting 
in  comparison  with  subsequent  results,  and  effectively  contrasts  the 
influence  of  skeletal  innervation  and  visceral  innervation  on  blood  pres- 
sure. 

b.  The  influence  of  the  cardiac  innervation  on  the  anemic  rise.  The 
influence  of  the  cardiac  nerves  on  the  anemic  rise  may  be  exerted  in 
either  of  two  ways.  The  change  in  rate  and  amplitude  of  the  heart 
beat  may  affect  the  output  per  minute  as  emphasized  by  Tigerstedt,  (57) 
or  afferent  impulses  aroused  within  the  heart  may  affect  reflexly  the 
efferent  cardio-vascular  innervation  as  discussed  by  Hill  (59).  It  is 
conceivable  that  in  either  of  these  ways,  or  both,  the  heart  may  influence 
significantly  the  level  of  blood  pressure. 

Frank  (57),  mathematically,  and  Erlanger  (58)  by  sphygmomano- 
metric  measurements,  have  attempted  to  show  that  the  output  of  the 
heart  remained  a  constant,  or  in  other  words  that  pulse  pressure  times 
pulse  rate  remains  a  constant.  Wickwire  (60)  has  shown  that  the 
usual  compensatory  changes  in  heart  rate  to  a  change  in  the  systemic 
blood  pressure  may  be  absent  in  deep  anesthesia  or  in  cases  of  restric- 
tion of  the  volume  of  blood  flow  to  the  brain.  Under  normal  circum- 
stances, Erlanger's  statement  probably  holds  true,  but  may  not 
necessarily  apply  under  critical  conditions. 

1.  Effect  of  the  vagus.  Mosso  (61),  Gouty- and  Stewart  found  that 
following  the  first  short  rise  in  blood  pressure  (which  in  the  intact  ani- 
mal is  never  very  great)  there  is  a  considerable  slowing  of  the  pulse. 
As  long  as  this  slowing  of  the  pulse  persists,  pressure  ceases  to  rise,  and 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL    ANEMIA  9 

is  indeed  often  lowered.  After  about  half  a  minute  of  this  effect,  the 
heart  seems  to  break  away  from  this  retardation,  and  the  beat  is,  if 
anything,  accelerated  and  pressure  immediately  rises  to  the  maximum 
level  which  is  maintained  until  its  final  fall.  The  slowing  of  the  heart 
rate  and  the  depression  of  blood  pressure  gives  the  anemic  rise  its 
typical  double  crest.  Both  Gouty  (16)  and  Stewart  (26)  saw  this 
double  crest  disappear  on  section  of  the  vagi,  leaving  a  smooth  curve, 
which  attains  its  maximum  height  somewhat  more  rapidly,  but  is  not 
otherwise  greatly  altered  in  time  or  intensity. 

Bilateral  vagotomy  has  been  done  only  incidentally  to  other  lesions. 
The  results  confirm  the  earlier  findings. 

2.  Excision  of  the  stellate  ganglia.  Section  of  the  accelerators  as  the 
only  lesion  was  undertaken  in  five  cats,  all  except  one  dissection  being 
made  in  the  open  thorax  under  artificial  respiration.  In  all  cases  the 
entire  stellate  ganglion  was  removed.  The  mass  of  nervous  tissue  was 
secured  by  a  hemostat  and  this  then  cut  away  from  all  the  connections 
by  which  it  was  held,  until  the  hemostat  could  be  removed  without 
tearing.  All  the  records  therefore  give  a  picture  of  the  effects  obtained 
by  excision  of  the  entire  ganglion  including,  of  course,  those  additional 
accelerator  fibers  recorded  by  Ranson,  Spadolini  and  Wickwire  (60), 
which  reach  the  stellate  ganglion  by  way  of  the  superior  cervical 
ganglion. 

Hunt  (62)  recorded  a  loss  of  pressure  on  section  of  the  stellate  ganglia. 
Wickwire  found  a  considerable  loss  (60  mm.)  on  their  section,  when  this 
was  undertaken  without  a  previous  vagotomy.  In  two  cats,  1  and  3, 
a  similar  depression  was  noted.  In  cat  2,  however,  the  fall  was  only 
20  mm.  In  cat  7,  in  which  pressure  was  already  very  low,  no  change 
at  all  was  noted. 

Section  of  the  accelerators  on  both  sides  seems,  like  double  vagotomy, 
to  have  a  typical  effect  on  the  contour  of  the  curve.  It  also  tends  to 
obliterate  the  double  nature  of  the  curve,  which  then  more  closely 
approaches  a  single  peak.  Characteristically,  section  of  the  accelera- 
tors imparts  to  the  anemic  rise  a  marked  plateau  effect.  After  a 
relatively  restricted  latent  period,  pressure  rises  sharply  to  its  maximum 
level  (fig.  1,  occlusion  2),  near  which  it  is  maintained  until  just  prior 
to  its  final  fall,  when  it  may  again  strike  the  greatest  height.  The 
anemic  increment  of  pressure  for  the  five  cats  examined  lay  between 
120  and  160  mm.  Hg.  Such  a  vagus  effect  as  made  itself  felt,  curiously 
enough,  appeared  somewhat  later  than  when  the  accelerators  were 
intact,  and  the  slowing  was  recorded  at  the  crest  of  the  wave  at  a  very 


10  CORA   SENNER   WINKIN 

high  level  of  blood  pressure.  Occasionally  a  sharp  depressor  effect 
may  be  recorded,  which  is  rapidly  compensated  for;  this  effect  gives  an 
M-shaped  appearance  to  the  curve.  On  the  whole,  with  the  stellate 
ganglia  excised,  pressor  responses  are  more  promptly  executed  and 
longer  maintained.  In  six  additional  cats,  section  of  the  accelerators 
was  complicated  by  other  lesions.  In  the  two  cases  in  which  it  was 
preceded  by  low  section  of  the  sympathetic  chain,  an  anemic  increment 
of  80  mm.  was  obtained  in  each. 


Fig.  1.  Cat  4;  Occlusion  1.  Cerebral  anemia,  anomalous  contour  of  curve. 
In  this,  great  fall  of  pressure  replaces  the  rise  ordinarily  obtained.  The  levels  of 
blood  pressure  before  anemia,  after  anemia  and  after  recovery  of  bulbar  function 
are  shown.  Head  arteries  were  released  immediately  after  the  rise  of  pressure, 
in  which  the  pre-occlusion  level  was  partially  recovered.  Pressure  fell  sub- 
sequently as  low  as  the  lowest  point  obtained  during  anemia,  but  regained  90  mm. 
above  this  level  with  the  return  of  bulbar  function. 

Occlusion  2:  Cerebral  anemia;  record  following  excision  of  both  stellate  gan- 
glia. When  anemia  is  induced,  pressure  is  50  mm.  lower  than  after  recovery  of 
bulbar  function,  prior  to  section  of  the  stellates;  M-shaped  curve,  showing  sharp 
immediate  rise  of  pressure,  almost  to  its  maximal  height;  vagus  effect  appears  at 
crest  of  wave.  Temporary  recovery  on  release  of  head  arteries,  followed  by  fall 
to  lowest  level  of  pressure  (55  mm.  Hg.  above  base  line) .  This  low  level  was  three 
times  reached  in  this  animal.  Final  rise  of  pressure  on  renewed  return  of  res- 
piration and  other  medullary  activities. 

Each  occlusion  occupied  3  minutes. 


CAKDIO-VASCTJLAR   CHANGES   DURING    CEREBRAL   ANEMIA  11 

3.  Excision  of  the  entire  cardiac  innervation.  In  three  cats  the  sec- 
t'on  of  both  vagi  and  accelerators  was  undertaken  without  any  previous 
lesion.  In  two  of  them,  section  of  the  vagi  was  undertaken  first,  and 
in  both  cases  a  rise  of  20  mm.  obtained.  Subsequent  section  of  the 
stellates  did  not  appreciably  lower  (by  more  than  5  mm.)  the  original 
level.  The  order  in  which  the  section  of  the  cardiac  nerves  is  carried 
out  is,  therefore,  significant  for  the  general  level  of  pressure,  and  is 
again  in  agreement  with  Miss  Wickwire's  findings.  Several  successive 
curves  were  obtained  from  cat  5.  The  anemic  increment  was  in  these 
cases  somewhat  reduced,  increments  of  80  to  100  mm.  being  obtained 
after  elimination  of  all  the  extrinsic  cardiac  nerves.  When  all  cardiac 
nerves  were  sectioned,  the  curve  tended  to  be  smooth,  the  initial  acute 
rise  not  being  at  all  delayed.  No  change  in  the  occlusion  time  was 
noted. 

Recovery  from  occlusion  after  excision  of  one  or  both  sets  of  the 
extrinsic  cardiac  nerves  was  uniformly  o.btained.  The  time  interval 
of  recovery  was  in  no  way  different  from  that  in  normal  animals. 

In  additional  cats  to  be  mentioned  later,  excision  of  the  extrinsic 
innervation  was  preceded  by  a  low  section  in  the  sympathetic  chain. 
One  animal  gave  an  even  higher  anemic  increment  (125  mm.  Hg.) 
than  is  usually  obtained  after  section  of  the  cardiac  nerves  alone. 

In  all  the  curves  of  reaction  to  anemia  from  animals  with  denervated 
hearts,  pressure  was  not  uniformly  maintained  at  the  maximal  level. 
In  two  cases  the  pressure  dropped  immediately;  in  the  rest  (4  cases) 
a  plateau  was  maintained. 

4-  Effect  of  the  cardiac  innervation  on  the  anemic  rise.  Neither  lesion 
of  the  cardiac  innervation,  as  a  whole,  nor  of  the  vagi,  nor  of  the  stellate 
ganglia  separately,  greatly  affects  the  blood  pressure  response.  Its 
duration  seems  to  be  fairly  constant  for  the  given  individual  tested. 
Excision  of  the  entire  cardiac  innervation  may  reduce  the  anemic  merer 
ment  in  some  cases,  but  the  reduction  when  it  occurs  does  not  seem  to 
be  considerable. 

However,  the  cardiac  nerves  seem  to  have  considerable  influence  on 
the  level  of  blood  pressure  in  the  more  detailed  relations  of  the  anemic 
rise,  especially  in  the  early  part  of  the  reaction.  From  the  results 
of  the  section  of  the  accelerators,  particularly  the  abruptness  with  which 
an  intense  rise  appears  immediately  on  occlusion  of  the  head  arteries, 
it  seems  that  the  conception  of  the  action  of  the  accelerators  must  be 
extended.  Marey  asserted  in  1881  that  with  the  vagus  intact  no  very 
great  rise  of  pressure  can  be  obtained.  Indeed,  as  long  as  the  vagi  are 


12  CORA   SENNER   WINKIN 

functional  the  maximal  anemic  increment  is  not  immediately  obtained, 
and  cannot  be  reached  in  tlie  early  part  of  the  occlusion  unless  the 
vagi  be  sectioned.  The  same  seems  to  follow  also  for  the  accelerators 
since,  when  they  are  removed,  the  vagus  cannot  prevent  the  immediate 
and  considerable  augmentation  of  pressure.  In  the  earlier  part  of  the 
anemic  response,  the  combined  action  of  the  entire  cardiac  innervation 
seems  to  effect  a  considerable  check  on  the  rapid  rise  of  blood  pressure. 
This  may  be  due  to  afferent  or  efferent  impulses,  but  the  accelerators 
seem  to  be  involved  as  well  as  the  vagi. 

The  relations  of  the  cardiac  innervation  to  the  second  rise  of  pressure 
are  not  so  clear.  Stewart  (28)  attributed  this  in  part  to  accelerator 
fibers  in  the  stellate  ganglion,  and  possibly  in  the  vagus,  but  recently 
Stewart  and  Rogofif  (63)  have  demonstrated  the  possibility  of  producing 


Fig.  2.  Cat  23;  cerebral  anemia.  Splanchnic  nerves  sectioned  at  their  entry 
to  coeliac  ganglia.  Occlusion  time  3  minutes.  Skeletal  convulsions  and  res- 
piratory spasms  evident.  The  only  factors  in  the  vascular  reaction  recognizable 
in  the  tracing  are  the  changes  in  heart  rate.  This  is  accompanied  by  a  very  slight 
•change  in  level  as  the  heart  is  breaking  away  at  the  usual  time  from  its  slow  rate. 
Two  respiratory  gasps  are  later  imposed  on  the  tracing. 

cardiac  acceleration  by  sciatic  stimulation  even  after  the  heart  is  com- 
pletely denervated.  In  this  series  of  experiments  the  rise  appears  very 
definitely  in  cats  with  accelerators  removed  and  vagus  intact.  It  must, 
therefore,  be  referable  to  vasomotor  or  endocrine  effects  under  these 
conditions.  Ordinarily,  there  is  no  break  in  the  curve  after  double 
vagotomy,  the  fall  due  to  vagus  slowing  being  absent.  In  two  cats, 
however,  such  a  second  rise  has  also  been  seen  when  the  heart  was  com- 
pletely denervated.  It  seems  that  the  cessation  of  the  vagus  effect, 
while  undoubtedly  significant,  is  only  one  of  the  factors  involved. 

In  the  absence  of  the  influence  of  tne  cardiac  nerves  on  the  initiation 
and  maintenance  of  the  reaction  to  cerebral  anemia,  it  seems  that  we 
must  look  to  the  vasomotor  mechanism  itself. 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  13 

It  is  interesting  to  note,  however,  that  when  the  animal  is  no  longer 
intact,  and  the  peripheral  resistance  has  been  markedly  lowered  by  a 
high  transection  of  the  cord,  these  relations  are  changed.  Yates  (36) 
has  observed  that  cats  which  showed  a  considerable  anemic  rise  after 
recovery  from  such  a  section,  completely  lost  their  ability  to  react  to 
cerebral  anemia  following  a  subsequent  excision  of  the  stellate  ganglia. 
However  important  for  all  practical  purposes  the  vasomotor  control 
may  be,  the  considerable  involvement  of  cardiac  factors  in  the  inte- 
grated response,  particularly  in  the  event  of  injury  to  the  vasomotor 
nerves,  must  not  be  overlooked. 

c.  Influence  of  the  splanchnic  nerves  on  the  anemic  rise.  The  wide 
distribution  of  the  splanchnics,  gives  a  possibility  for  various  lesions 
within  the  system.  Section  of  the  splanchnics  was  therefore  undertaken 
1,  in  the  base  of  the  sympathetic  chain  before  leaving  the  thorax;  2,  in 
the  abdomen,  just  prior  to  their  entrance  into  the  coeliac  ganglion; 
3,  in  various  levels  of  the  spinal  cord  in  the  thoracic  region. 

The  anatomical  relations  of  the  splanchnic  outflow  in  the  cat  have 
been  described  by  Langley  (64),  who  concludes  that  the  fibers  destined 
to  enter  the  splanchnic  nerves  leave  the  cord  in  large  part  below  the 
level  of  the  sixth  thoracic,  though  occasionally  fibers  can  be  traced  at 
the  level  of  the  fifth  and  even  fourth  thoracic.  Langley's  statement 
appears  based  only  in  part  on  his  own  observations,  and  is  largely 
founded  on  the  work  of  other  investigators  embodied  in  the  papers 
quoted.  Several  authors  included  higher  levels  for  the  effects  studied 
based  on  experimental  rather  than  anatomical  evidence  though  all 
have  stated  that  the  effect  elicitable  is  relatively  slight.  Bayliss  and 
Starling  gave  3rd  thoracic  as  supplying  the  portal  circulation,  Bradford, 
the  3rd  thoracic  as  supplying  the  kidney;  and  Schafer  and  Moore, 
3rd  thoracic  as  supplying  the  spleen. 

In  a  more  recent  study  on  cats  Ranson  (65)  has  re-investigated  the 
problem.  He  confirms  Langley's  findings  and  considers  the  4th  thor- 
acic the  highest  limit  of  the  splanchnic  outflow.  Ranson's  material, 
however,  was  in  part  restricted  to  animals  in  which  only  the  levels 
below  the  6th  thoracic  were  examined.  Ranson  has  investigated  fur- 
ther the  level  at  which  the  splanchnic  nerve  leaves  the  sympathetic 
chain.  In  far  the  greater  number  of  cases  (13  out  of  17)  the  nerve  was 
given  off  between  the  1st  lumbar  and  13th  thoracic  ganglion,  in  the 
remaining  four  cases,  the  nerve  left  between  the  1st  and  2nd  lumbar 
ganglia.  The  relation  of  this  branching  to  the  diaphragm  was  not 
stated. 


14  CORA   SENNER   WINKIN 

1.  Lesions  within  the  splanchnic  outflow:  Section  of  the  sympathetic 
chain;  thoracic  section  of  the  splanchnics.  In  12  animals  the  splanchnic 
outflow  was  interrupted  in  the  lower  thorax.  Under  artificial  respira- 
tion, a  low  midventral  incision  was  extended  bilaterally  on  either  side 
of  the  diaphragm,  and  the  lungs  held  back  while  the  sympathetic  chain 
was  isolated  and  sectioned. 

Section  of  the  sympathetic  chain  below  the  level  of  the  8th  or  9th 
thoracic  vertebrae  usually  gives  a  very  marked  fall  of  pressure. 
When  the  splanchnic  branch  from  the  sympathetic  chain  itself  is  cut, 
this  depression  amounts  at  least  to  80  mm.  Hg.  In  spite  of  this  low 
level  of  pressure,  spontaneous  respiration  is  not  usually  lost,  and  wrhen 
ether  is  reduced,  eye  reflexes  and  other  skeletal  responses  are  readily 
elicitable.  The  condition  of  the  animal,  however,  is  precarious,  and 
prolonged  operative  manipulations  with  too  great  a  depth  of  anes- 
thesia will  readily  cause  complete  loss  of  the  bulbar  responses.  This 
precarious  .condition  is  in  fact  met  with  in  all  extended  lesions  within 
the  splanchnic  system,  and  offers  some  difficulty  in  the  further  manip- 
ulation of  the  animals. 

Occlusion  of  the  head  arteries  in  this  series  generally  gave  a  relatively 
vigorous  response.  The  intensity  of  the  response  varied,  the  degree 
of  variation  from  the  normal  being  dependent  apparently  on  the  nature 
of  the  lesion. 

Group  I.  In  these  animals  section  of  the  sympathetic  chain  was 
undertaken  in  its  lower  levels,  post-mortem  examination  showing  no 
lesion  above  the  level  of  the  8th  thoracic.  In  two  of  these  animals 
autopsy  showed  the  lesion  incomplete  on  one  side,  thus  amounting 
largely  to  a  unilateral  injury.  The  anemic  response  obtained  in  four 
of  these  animals  was  very  considerable,  the  values  being  100,  120,  140, 
150  mm.  Hg.,  respectively.  The  contour  of  the  curves  was  typical  of 
the  normal  anemic  responses,  and  the  rise  of  pressure  easily  over-reached 
the  original  control  level  of  blood  pressure.  All  these  cats  showed  a 
normal  recovery  from  the  occlusion.  In  nos.  12  and  15,  excision  of  the 
stellate  ganglia  was  done  subsequent  to  recovery  and  a  third  occlusion 
obtained.  Cat  15  that  had  shown  an  unusually  vigorous  response  in 
its  first  occlusion  gave  an  increment  of  125  mm.  Hg.  after  excision  of 
both  vagi  and  both  stellates.  The  thoracic  chain  was  sectioned  at  the 
level  of  the  8th  and  9th  thoracic  on  one  side,  between  the  10th  and  llth 
on  the  other.  Cat  11  was  slightly  different.  The  original  depression 
of  blood  pressure  after  section  of  the  chain  was  80  mm.  Hg.;  the  anemic 
increment  was  somewhat  reduced,  amounting  only  to  70  mm.  so  that 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  15 

the  anemic  rise  fell  short  of  reaching  the  original  level.  The  cat 
recovered,  however,  and  subsequently  made  up  the  10  mm.  difference 
in  an  anemic  rise  obtained  after  the  stellate  ganglia  had  been  excised. 
The  greater  splanchnics  may  have  been  involved  in  this  case. 

Group  II.  This  comprised  the  remaining  7  cats  of  the  series.  In 
all  these  animals  a  complete  bilateral  section  of  the  splanchnic  nerves 
was  done  in  the  thorax  between  their  branching  from  the  sympathetic 
chain  and  before  their  entry  into  the  diaphragm.  On  cutting  the 
splanchnic  nerves  the  initial,  fall  of  pressure  was  great,  averaging  80 
mm.  In  four  cats  the  effect  of  occlusion  was  well  marked,  the  curves 
differing  from  the  normal  only  in  a  slight  reduction  of  the  anemic 
increment  of  blood  pressure,  this  being  70  mm.  in  three  cases. 
In  these  cases  also  pressure  did  not  reach  the  level  held  prior  to  section. 

In  the  three  remaining  cats  of  the  series  a  still  greater  depression 
of  the  anemic  response  was  obtained.  Cat  20  gave  a  most  complete 
picture.  The  anemic  rise  reduplicated  all  the  characteristics  of  the 
normal  response  on  a  smaller  scale.  A  vagus  effect  appeared  promi- 
nently. The  maximum  anemic  increment  of  pressure  in  these  experi- 
ments was  40  mm.  When  pressure  fell  spontaneously  after  occlusion 
it  reached  the  identical  level  maintained  after  section  of  the  splanchnics 
prior  to  occlusion.  Low  section  of  the  spinal  cord  at  this  time  induced 
a  further  fall  of  only  10  mm.  Hg.  In  cat  22  the  acclerators  were  also 
removed,  and  an  even  greater  depression  of  the  anemic  response  was 
obtained,  the  entire  change  of  level  on  occlusion  amounting  to  only 
5  mm. 

Cat  21  was  slightly  anomalous  but  yet  highly  instructive.  The 
animal  showed  a  great  resistance  to  anemia,  and  it  took  some  15  minutes 
before  the  respiratory  and  vasomotor  responses  fully  faded  out.  At 
first  the  Record  clearly  approximated  that  of  cat  20,  an  initial  rise  of 
30  mm.  being  shown.  With  the  parsistence  of  the  bulbar  functions, 
however,  there  was  reproduced  on  a  different  scale,  the  wide  oscilla- 
tions procurable  in  all  animals  difficult  to  asphyxiate.  At  first  the 
vasomotor  oscillations  were  slight  and  rather  irregular,  but  they  grad- 
ually developed  into  large  and  rapid  waves  in  which  the  greatest  ex- 
cursion of  blood  pressure  was  developed,  amounting  to  a  fluctuation  of 
60  mm.  at  the  height  of  the  response.  The  level  of  blood  pressure 
from  which  these  oscillations  developed  was  not  raised,  the  whole 
response  being  simply  recorded  within  this  maximum  variation  of 
60  mm.  This  offers  a  striking  contrast  to  the  analogous  records  of 
incomplete  occlusion  periods  of  similar  length  obtained  in  intact  ani- 


16  CORA   SENNER   WINK1N 

mals.  In  such  animals  the  level  of  pressure  shows  similar  oscillations, 
but  these  vary  within  a  much  greater  range,  usually  approaching  200 
mm.  difference  in  level.  No  recovery  of  bulbar  functions  was  elicited 
from  any  of  these  animals.  That  this  was  not  the  necessary  conse- 
q/uence  of  a  lesion  at  this  level,  but  merely  an  indication  of  the  precarious 
conditions  of  animals  exposed  to  this  double  lesion,  is  shown  in  the 
following  experiments. 

Section  of  the  sympathetic  chain;  abdominal  section  of  the  splanchnics. 
Although  the  blood  pressure  response  is. seriously  reduced  by  section 
of  the  splanchnic  nerves  above  the  diaphragm,  a  slight  degree  of  re- 
sponse still  seems  elicitable.  It  seems  possible,  however,  completely 
to  eliminate  all  rise  of  blood  pressure  as  the  result  of  bulbar  anemia, 
while  maintaining  all  other  evidence  of  medullary  activity,  by  section  of 
the  greater  splanchnic  nerves  in  the  abdomen. 

Dissection  for  the  splanchnics  in  the  abdomen  was  made 'by  the 
method  indicated  in  Sherrington's  Mammalian  Physiology  (66).  The 
incisions  were  made  from  the  back,  through  the  latissimus  dorsi  mus- 
cles, and  the  nerves  were  cut  just  before  their  entry  into  the  coeliac 
ganglion.  The  identity  of  the  nerves  was  first  tested  by  electrical 
stimulation  with  shielded  electrodes. 

A  striking  example  of  the  result  of  this  section  was  obtained  in  cat 
23.  In  this  animal  (fig.  2)  the  greatest  excursion  of  blood  pressure 
amounted  to  10  mm.,  yet  all  other  effects  of  occlusion  were  noted.  An 
asphyxial  effect  on  the  vagi  appeared  in  the  pressure  curve  followed  by 
a  very  slight  improvement  in  the  level.  From  this  point  on,  however, 
pressure  fell  very  gradually,  until,  at  the  end  of  3  minutes,  it  remained 
constant.  In  this  very  gradual  fall,  pressure  reached  a  level  some 
20  mm.  below  that  of  the  original  pressure  before  occlusion.  After 
digital  compression  of  the  abdominal  aorta,  spontaneous  respiration 
returned  in  this  animal.  When  respiration  had  become  completely 
reestablished  and  a  corneal  reflex  again  obtained,  the  trachea  was 
clamped.  No  asphyxial  rise  of  pressure  to  speak  of  was  obtained,  the 
entire  subsequent  variation  of  pressure  being  well  within  20  mm.  Hg. 
Respiratory  waves  and  some  vagus  effect  were  recorded;  failure  of  the 
heart  soon  followed. 

Section  of  the  thoracic  spinal  cord.  Section  of  the  spinal  cord  was 
undertaken  in  16  cats.  The  laminectomy  was  carried  out  immediately 
following  tracheotomy,  the  wipund  temporarily  closed  by  hemostats 
and  the  head  arteries  then  prepared  for  ligation.  Finally  the  cord 
was  sectioned,  and  blood  pressure  allowed  to  reach  a  constant  level 


CARDIOVASCULAR    CHANGES   DURING    CEREBRAL   ANEMIA 


17 


before  inflicting  any  further  lesions.  Several  successive  sections  of  the 
cord  were  frequently  carried  out  in  the  same  animal  before  occlusion 
was  produced. 

Section  of  the  thoracic  cord  was  carried  out  at  various  levels.  The 
effect  of  section  varied  considerably  with  the  level  of  the  lesion,  and  to 
some  extent  also  with  the  individual  animal.  Certain  results,  however, 
are  patent.  Lesion  in  the  lowest  levels  of  the  thorax  elicited  only  a 
slight  permanent  fall  of  pressure,  and  did  not  seriously  affect  the  anemic 
response.  Lesions  in  the  midthoracic,  at  the  level  of  the  8th  thoracic 
and  9th  thoracic  vertebrae  were  more  apt  to  elicit  a  profound  fall  of 
pressure,  and  seriously  to  reduce  the  anemic  increment.  Lesions  in 
the  upper  thorax  also  elicited  a  great  fall  on  section  and  often  completely 


Fig.  3.  Cat  30:  cerebral  anemia.  Spinal  cord  sectioned  at  the  level  of  the  5th 
thoractic  verterbra.  This  reaction  shows  the  features  of  the  typical  blood  vas- 
cular response  to  anemia  in  every  respect,  but  the  level  to  which  the  maximal 
rise  of  pressure  (second  rise)  attains.  The  anemic  increment  here  is  only  50  mm. 
Hg.  Cardiac  effects  of  slowing  and  acceleration  recorded  as  usual. 

abolished  the  rise  of  pressure.  There  were,  however,  certain  individuals 
in  which  even  a  high  thoracic  lesion  did  not  evoke  a  maximum  fall  of 
pressure,  and  in  which  a  relatively  vigorous  response  was  obtained  even 
after  a  high  dorsal  section.  Accordingly  the  experimental  material 
can  be  roughly  classified  into  three  groups: 

Group  I.  Lesions  in  the  lower  thoracic  region.  Very  vigorous  responses 
to  cerebral  anemia  can  still  be  obtained  from  animals  with  a  lesion  at 
the  level  of  the  10th  to  12th  thoracic  vertebrae.  Cat  25  with  section 
at  T  10-11  showed  an  anemic  increment  of  125  mm.  Hg.  In  cat 
24  an  anemic  response  lasting  over  5  minutes  was  obtained,  in  which 
the  variation  of  pressure  extended  over  75  mm.  Hg.  The  contour  of 


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CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  23 

this  curve  will  be  discussed  below  in  connection  with  similar  anomalous 
curves  obtained  from  control  records  in  other  animals.  In  these  cats 
a  fall  of  pressure  replaces  the  usual  rise;  the  variation  of  level  being 
of  the  same  order  of  magnitude.  In  cat  24,  despite  the  great  drop  of 
pressure,  the  original  level  was  regained  toward  the  end  of  the  anemic 
response  at  the  time  usually  occupied  by  the  second  rise  of  pressure. 

Measurements  of  loss  of  pressure  after  section  in  the  lowest  levels 
of  the  thorax  show  a  maximal  total  loss  of  50  mm.  Hg.  Frequently 
only  a  few  millimeters  are  lost.  In  cat  30  the  10  mm.  lost  after  section 
at  the  10th  thoracic  were  completely  recovered  within  10  minutes, 
pressure  rising  even  above  the  level  recorded  prior  to  transection. 

Group  II.  Abolition  of  the  anemic  response.  Lesions  of  the  cord 
in  the  region  of  the  8th  thoracic  usually  entail  a  rather  severe  effect; 
the  loss  of  pressure  following  this  section  may  amount  to  80  mm.  Hg. 
If  the  fall  is  as  great  as  this,  the  anemic  response  is  apt  to  be  seriously 
diminished.  Cat  25,  which  gave  a  very  vigorous  response  after  section 
at  T  10,  showed  a  further  loss  of  80  mm.  when  the  cord  was  sectioned 
at  T  8,  the  level  falling  100  mm.  below  that  held  when  the  animal  was 
intact.  The  anemic  increment  after  section  at  T  8  was  only  30  mm. 
Hg.  The  reduction  of  the  anemic  increment  to  a  variation  of  pressure 
of  only  30  to  40  mm.  was  seen  in  five  other  experiments,  (cats  24,  30, 
38,  40,  and  42)  in  which  section  in  the  region  of  the  8th  to  10th  thoracic 
gave  a  considerable  depression  of  the  level  of  blood  pressure  and  in 
which  anemia  of  the  bulb  failed  to  evoke  an  increment  of  pressure 
greater  than  40  mm.  That  the  vagus  is  partially  responsible  for  this 
effect  is  indicated  by  cat  42,  in  which  an  initial  response  after  section 
in  the  8th  thoracic  gave  an  increment  of  only  20  mm.  This  increment, 
however,  rose  slightly  above  40  mm.  in  a  subsequent  occlusion  after 
the  vagi  had  been  sectioned. 

Section  of  the  cord  above  the  8th  thoracic  in  three  animals,  cats  35, 
39  and  44,  gave  a  very  marked  fall  of  pressure  in  all  these  cases  and  no 
anemic  response  greater  than  30  mm.  was  obtainable  in  any  one  of 
them.  In  cat  44,  only  one  section  was  made  at  T  6,  and  no  anemic 
increment  at  all  was  obtainable  after  occlusion.  In  the  other  two  ani- 
mals several  successive  sections  were  undertaken  before  occlusion  was 
tested.  In  cat  39,  the  first  section  was  carried  out  at  T  7;  this  was 
followed  by  a  fall  of  55  mm.;  40  mm.  more  were  lost  in  successive  sec- 
tions ascending  to  the  level  of  T  4.  In  cat  35,  80  mm.  were  lost  by 
section  at  T  8,  and  only  20  mm.  more  by  successive  sections  to  T  6. 
The  level  of  pressure  above  base  line  from  which  only  a  minimal  sub- 


24  CORA   SENNER   WINKIN 

sequent  fall  occurs  under  further  manipulations,  lies  between  35  to  50 
mm.,  the  residual  pressure  maintained  by  the  spinal  cord  alone. 

Group  III.  Retention  of  an  anemic  effect.  The  midthoracic  region 
is  apparently  not  critical  for  vasomotor  responses  in  all  animals.  In 
cat  34  section  at  the  8th  thoracic  gave  a  loss  of  only  30  mm.  Hg.  and 
an  anemic  increment  of  68  mm.  Hg.  was  obtained.  The  relatively 
slight  loss  of  pressure  following  section  at  T  7  in  cat  39  above  mentioned 
also  shows  that  in  some  animals  the  higher  levels  of  the  cord  are  of 
great  importance. 

However,  the  most  significant  indication  of  participation  of  the  upper 
levels  of  the  cord  in  conveying  fibers  significant  for  the  vasomotor 
response  was  obtained  in  four  additional  animals.  A  strikingly  com- 
plete anemic  rise  was  obtained  from  cat  30,  in  which  the  cord  had  been 
sectioned  as  high  as  T  5  (fig.  3) .  The  anemic  increment  here  was  54 
mm.  In  cat  38  a  well-maintained  response  of  44  mm.  was  obtained  on 
occlusion  after  section  at  T  6.  In  cat  31  a  rise  of  the  same  magnitude 
(40  mm.)  was  obtained  after  section  at  T  2.  The  level  maintained 
after  section  at  T  2  prior  to  occlusion  was  65  mm.  Hg.  above  base 
line  and  did  not  reach  the  level  of  50  mm.  until  after  occlusion.  An 
interesting  record  of  the  potency  of  the  higher  levels  in  certain  indi- 
viduals for  both  the  maintenance  of  blood  pressure  and  its  variation  is 
best  given  in  the  following  protocol — cat  40. 

Condensed  protocol,  cat  40  (pressure  here  given  in  level  above  base  line)  April  22,  1918 

Tracheotomy,  blood  pressure,  cannula,  laminectomy,  head  arteries  prepared 

for  ligation. 

2:30    Control  blood  pressure — 130  mm.  Hg. 

2:35    Section  of  cord  at  T  8 

2:40    Level  of  blood  pressure — 118  mm.  Hg. 

2:45    Section  of  cord  at  T  6 

2:47    Level  of  blood  pressure — 90  mm.  Hg.,  total  depression  of  pressure — 40  mm. 

2:48    Corneal  reflex 

Occlusion.     Sharp  rise  of  pressure  to  114  mm.  drop  to  90  mm.  Hg.,  great 
vagus  effect,  rise  again  to  130  mm.:  anemic  increment — 40  mm. 

2:51     Pressure  released  before  spontaneous  fall  began,  gasps  immediately  return, 
fall  to  80  mm. 

2:57    Respiration  reestablished,  section  of  cord  at  T  5 

2:58    Level  of  blood  pressure — 70  mm.  Hg.,  total  depression  of  pressure — 60  mm. 

2:59    Corneal  reflex,  occlusion: — -incomplete 

3:01     Further  manipulation  of  clamps,  immediate  rise  of  pressure  to  114  mm., 
anemic  increment — 44  mm. 

3:04    Released  before  spontaneous  fall,  pressure  drops  to  50  mm.  Hg.,  but  imme- 
diately begins  again  to  recover 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  25 

3:05    Gasps  return,  pressure  continues  rising 

3:10    Pressure  reaches  90  mm.  Hg.  again,  regular  waves  in  blood  pressure  curve, 
respiration  reestablished 

3 : 17    Section  of  cord  at  T  4,  pressure  drops  to  70  mm. 

Corneal  reflex,  Occlusion:  sharp  rise  of  pressure  to  100  mm.  fall  to  60  mm. 
during  vagus  slowing,  subsequent  rise  to  112  mm.;  anemic  increment — 
42  mm. 

3:23    Pressure  released  before  spontaneous  fail,  drops  sharply  to  44  mm.  but 
immediately  begins  to  rise  again 

3:25    Gasps  return 

3:33     Pressure  at  84  mm.  again,  respiration  reestablished 

3:39    Section  of  cord  at  T  2,  pressure  falls  to  46  mm.  Hg.  total  depression  of  pres- 
sure, 84  mm. 

3:40    Corneal  reflex,  Occlusion:  initial  rise  to  64  mm.  Hg.  fall  to  30  mm,  during 
vagus  slowing,  second  rise  to  74  mm.  Hg.  anemic  increment — 28  mm. 

3:42    30  Head  arteries  released  before  spontaneous  fall,  pressure  immediately 
falls  to  20  mm.  but  again  regains  level 

3:45    Pressure  has  reached  54  mm.,  gasps  return,  further  rise  to  60  mm.  respira- 
tion reestablished 
Thorax  opened,  artificial  respiration  administered 

4:05    Sympathetic  chain  cut  in  midthoracic,  pressure  fall  to  40  mm.  total  depres- 
sion of  pressure — 90  mm. 

4:07    Corneal  reflex:  occlusion,  rise  to  52  mm.  slight  fall,  rise  to  48  mm.  anemic 
increment — 12  mm. 

4:11    Release  of  head  arteries,  pressure  drops  to  30  mm. 

4:14    Gasps  return,  pressure  rises  to  40  mm.  respiration  reestablished 

4:55    Splanchnics  cut  in  psoas  muscles,  no  effect  on  blood  pressure,  no  recovery 
of  level  or  return  of  respiration 

5:10    Artificial  respiration  intermitted,  pressure  drops  to  base  line. 

Effect  of  the  splanchnic  constrictor  fibers  on  the  anemic  rise.  The  bur- 
den of  the  anemic  response  seems  to  lie  in  the  vasomotor  apparatus, 
and,  if  the  evidence  of  these  experiments  is  adequate,  almost  exclusively 
on  the  splanchnic  constrictor  fibers.  Peripheral  section  of  the  splanch- 
nic nerves,  with  its  great  depression  of  blood  pressure,  and  the  sub- 
sequent inability  to  obtain  any  anemic  increment  whatever,  speaks 
strongly,  almost  unequivocally,  for  such  an  interpretation.  Additional 
evidence  for  the  importance  of  the  splanchnic  pathway  for  the  vaso- 
motor changes  during  anemia  is  the  relation  of  the  level  of  blood  pressure 
after  section  within  the  splanchnic  outflow  to  the  anemic  increment 
elicitable  on  occlusion.  The  data  show  quite  clearly  that  the  greater 
the  initial  depression,  the  less  powerful  the  response. 

This  very  definite  grading  of  the  blood  pressure  level  to  the  magni- 
tude of  the  anemic  rise  gives  a  further  insight  into  the  anatomical 
relations  of  the  splanchnic  outflow.  In  the  cats  examined  the  greatest 


26 


CORA   SENNER    WINKIN 


Fig.  4.  Cat.  45.  Repeated  cerebral  anemia;  double  vagotomy;  10th  successive 
occlusion;  dissociation  of  reaction  curve  into  two  distinctly  separated  peaks  is 
shown  fully  established.  Second  peak  in  this  occlusion  is  still  considerably 
greater  than  the  first.  Pressure  falls  very  low  at  the  end  of  the  response  (30  mm. 
Hg.  above  base  line).  Each  curve  occupies  approximately  half  the  period  of  the 
reaction. 

Seventeenth  successive  occlusion:  Dissociated  curves  show  little  difference 
in  time  relations  compared  with  those  obtained  2  hours  earlier.  Difference  in 
contour  found  in  the  greater  emphasis  of  the  first  as  compared  with  the  second 
peak  of  pressure.  The  rise  in  level  prior  to  occlusion  represents  the  recovery  of 
blood  pressure  after  the  preceding  occlusion  following  the  return  of  respiratory 
gasps. 


CARDIOVASCULAR   CHANGES   DURING    CEREBRAL   ANEMIA  27 

average  ouflow  from  the  cord  to  the  sympathetic  chain  is  apparently 
in  the  region  of  the  6th  to  8th  thoracic.  Yet  the  outflow  is  not  restricted 
to  the  lower  thoracic  region,  for  fibers  in  the  higher  thoracic  region  even 
as  high  as  the  1st  or  2nd,  have  in  these  experiments  been  found  of  some 
importance  both  for  the  maintenance  of  the  level  and  the  changes 
of  blood  pressure.  Such  a  curve  as  that  obtained  from  cat  30  (fig.  3) 
shows  convincingly  that  in  some  animals  a  good  proportion  of  fibers 
leave  the  spinal  cord  to  enter  the  sympathetic  chain  above  the  level  of 
the  5th  thoracic  vertebra. 

While  therefore  the  anatomical  findings  of  Langley  and  Ranson  for 
the  average  level  of  outflow  have  in  the  main  been  verified,  the  involve- 
ment of  higher  levels  already  indicated  by  the  various  physiological 
researches  quoted  by  Langley  has  received  a  rather  striking  con- 
firmation. 

In  such  an  instance,  the  physiological  evidence  may  well  have  pre- 
cedence over  the  anatomical,  for  whereas  a  small  bundle  of  fibers  is 
most  difficult  to  stain  and  trace  microscopically,  a  weak  physiological 
effect,  when  definitely  isolated,  is  quite  unmistakable.  The  involvement 
of  these  fibers  from  the  higher  levels  within  the  splanchnic  system,  be- 
comes of  particular  importance  when  the  entire  burden  of  the  splanch- 
nic function  is  restricted  to  these  levels.  Since  the  very  high  out- 
flow presumably  goes  by  way  of  the  stellate  ganglion,  it  is  necessary  to 
differentiate  between  the  effect  of  the  splanchnic  fibers  proper  and  the 
accelerators.  However,  in  these  cats  in  which  an  abdominal  or  high 
spinal  section  completely  abolished  the  rise,  the  cardiac  nerves  seemed 
completely  impotent  against  the  lowered  peripheral  resistance. 

Accordingly,  the  vasomotor  impulses  that  travel  through  the  splanch- 
nic nerves  to  the  coeliac  ganglion  may  leave  the  cord  as  high  as  the 
first  or  second  thoracic.  They  may,  however,  stay  in  the  cord  through- 
out the  thoracic  region  and  leave  it  even  below  the  diaphragm.  Ran- 
son 's  results  on  the  very  low  level  at  which  the  splanchnic  nerve  leaves 
the  chain  in  cats,  is  in  close  agreement  with  these  findings. 

There  thus  appears  to  be  a  double  pathway  for  the  splanchnic  out- 
flow in  the  thorax,  one  within  the  cord,  the  other  outside  of  it.  The 
outflow  of  the  splanchnic  fibers  from  the  cord  to  the  sympathetic  chain 
seems  distributed  over  the  entire  thoracic  region,  the  relative  distribu- 
tion varying  from  one  individual  to  another. 

In  this  light  the  impossibility  of  abolishing  the  anemic  rise  by  a  sec- 
tion which  implicates  only  part  of  the  splanchnic  system  is  explicable. 
The  wide  distribution  of  the  splanchnic  fibers  would  make  it  difficult 


28  CORA   SENNER   WINKIN 

to  compromise  the  response  by  a  definitive  lesion.  Such  a  lesion  could, 
it  seems,  be  secured  only  when  the  section  falls  sufficiently  far  out  in 
the  periphery  or  sufficiently  high  up  in  the  cord,  definitely  to  interrupt 
the  conduction  pathways  from  medulla  to  coeliac  ganglion.  Unless  this 
interruption  is  accomplished,  the  fibers  that  are  left  in  continuity  with 
the  medulla  and  the  periphery  are  able  to  initiate  an  anemic  rise  which, 
even  if  considerably  diminished  in  intensity,  repeats  all  other  char- 
acteristics of  the  usual  vasomotor  response. 

To  the  splanchnic  innervation,  therefore,  the  most  significant  fac- 
tors in  the  blood  vascular  reaction  to  cerebral  anemia  can  be  attrib- 
uted: the  initiation  of  the  rise  and  the  level  which  this  reaches.  Since 
these  factors  can  be  controlled  by  differential  lesions  within  the  splanch- 
nic system,  the  influence  of  the  non-splanchinc  vasomotors  may  be 
neglected  for  the  purposes  of  the  present  survey. 

On  the  influence  of  the  splanchnic  system  on  the  maintenance  of  the 
normal  level  of  blood  pressure:  The  splanchnic  fibers  seem  involved  when 
the  level  of  pressure  is  above  50  to  60  mm.  for  unless  a  complete  interrup- 
tion of  the  conduction  path  from  medulla  to  coeliac  ganglion  has  been 
demonstrated,  pressure  returns  to  a  higher  level  the  height  depending 
apparently  on  the  number  of  fibers  in  the  splanchnic  system  remaining 
functional.  The  level  of  50  to  60  mm.  is  that  shown  by  Mayer,  Gouty 
and  later  workers  to  be  that  maintained  by  the  spinal  cord  alone.  Yates 
also  finds  this  level  to  be  approximately  that  reached  by  blood  pressure 
after  recovery  (2  to  32  days)  from  high  transection  of  the  spinal  cord 
at  8th  cervical  to  5th  thoracic.  Her  average  level  of  pressure  lay  some- 
what lower  than  this,  between  40  to  50  mm.  From  Pike's  and  Langley's 
studies  this  residual  spinal  level  appears  rather  as  a  skeletal  or  somatic, 
than  as  a  vascular  or  sympathetic  phenomenon. 

The  difference  between  the  residual  spinal  level  and  the  normal  one — 
a  difference  of  80  to  100  mm. — would  therefore  appear  as  accounted 
for  largely  by  the  action  of  the  sympathetic  neurones  within  the  splanch- 
nic system.  When  the  range  of  variation  during  anemia  is  examined, 
this  is  seen  to  be  three  to  four  times  as  great  in  the  animal  with  splanch- 
nics  intact  as  in  the  animal  which  is  largely  dependent  on  its  skeletal 
musculature.  The  variation  of  pressure  in  cats  with  low  thoracic 
section  of  the  sympathetic  chain  is  greatly  restricted  where  the  animal 
was  highly  resistant  to  anemia  and  a  period  as  long  as  15  minutes  elapsed 
before  the  processes  activated  by  the  higher  levels  ceased.  Further- 
more, as  long  as  the  splanchnic  system  is  functional,  pressure  does  not 
drop  below  the  level  of  50  to  60  mm.  Hg.,  however  great  the  variation 


CARDIOVASCULAR  CHANGES  DURING  CEREBRAL  ANEMIA      29 

of  pressure  and  no  matter  how  exigent  the  inimical  conditions.  This  is 
well  illustrated  by  the  variation  of  pressure  noted  in  figure  3.  The  pro- 
tocol of  cat  40  where  pressure  in  maintained  in  excess  of  60  mm.  until 
after  a  section  of  the  spinal  cord  at  the  level  of  the  4th  thoracic,  also 
emphasizes  the  relation  of  this  level  to  splanchnic  activity. 

On  some  anomalous  curves.  In  a  relatively  large  number  of  cats 
(8  in  60)  a  depression  of  blood  pressure  was  obtained  on  occlusion  in- 
stead of  the  usual  anemic  increment.  This  depression  of  the  level  of 
blood  pressure  was  great,  approaching  the  order  of  magnitude  of  the 
usual  positive  effect.  In  six  of  these  cats,  pressure  fell  100  mm.  and 
more  below  the  original  level  of  blood  pressure.  Most  of  these  curves 
represented  control  occlusions,  one  example  of  which  has  been  figured 
(fig.  1,  occlusion  1)  in  which  no  previous  lesion  had  been  inflicted  the 
vagi  being  intact  in  'all  cases.  In  one  case,  cat  24,  also  mentioned, 
this  depression  appeared  after  low  section  of  the  spinal  cord.  In  these 
cats  on  occlusion  there  followed  no  initial  increment,  or  only  a  very 
slight  increase  in  the  level  (5  mm.).  Pressure  then  continued  constant 
foi  some  20  seconds.  Following  this  a  great  and  very  rapid  fall  of 
blood  pressure  set  in  from  which  recovery  occurred  at  about  the  time 
ordinarily  occupied  by  the  second  rise  of  blood  pressure.  In  this  recov- 
ery from  the  low  level  of  blood  pressure,  however,  pressure  approached 
but  never  completely  attained  the  original  level  observed  before 
occlusion. 

The  magnitude  of  the  effect  might  argue  for  the  involvement  of  the 
splanchnic  system.  As  such,  it  might  be  aroused  by  an  afferent  excita- 
tion of  the  depressor  fibers  in  the  vagus.  The  relation  of  the  depressor 
to  the  splanchnic  system  and  also  to  the  discharge  of  adrenalin  (which 
would  of  course  be  involved  in  all  splanchnic  excitation)  has  been  dis- 
cussed by  Ludwig  and  Cyon  (48)  and  Oliver  and  Schafer.  Bayliss 
(67)  has  dealt  with  the  antagonism  of  asphyxia  and  depressor 
stimulation. 

On  the  other  hand,  the  depression  of  blood  pressure,  instead  of  being 
due  to  the  cardiac  innervation  set  into  action  through  an  afferent  chan- 
nel, might  be  affected  directly  through  a  change  in  the  minute  volume 
of  the  heart,  especially  under  changed  conditions  within  the  vagus  sys- 
tem. Wickjvire  (60)  has  particularly  noticed  that  different  degrees 
of  the  depth  of  anesthesia  gravely  influence  the  changes  in  the  level  of 
blood  pressure  due  to  the  vagus  system. 

II.  RELATION  OF  THE  ADRENAL  GLANDS  TO  THE  RISE  OF  PRESSURE 
DURING  CEREBRAL  ANEMIA.  The  extensive  involvement  of  the  splanch- 


30  CORA   SENNER   WINKIN 

nic  system  in  the  anemic  response  makes  the  activity,  or  some  pro- 
duct of  the  activity,  of  the  adrenal  glands  of  considerable  significance 
for  the  problem  of  its  control.  Following  the  discovery  by  Oliver  and 
Schafer  (68)  of  the  pressor  action  of  injected  extract  of  adrenal  tissue, 
workers  have  tended  to  emphasize  the  close  physiological  relation  of 
the  glands  and  their  pressor  activity  to  the  splanchnic  system.  The 
literature  is  extensive  (69),  (70),  (71),  (72),  (73),  (74),  (75),  but  it  will 
not  be  reviewed  at  this  time.  Nor  will  the  literature  on  the  liberation 
of  adrenalin  (75  to  90)  be  considered  here.  The  evidence  for  the  parti- 
cipation of  adrenalin  in  the  response  to  asphyxia  and  other  conditions 
of  stress  is  also  extensive  (91  to  98),  but  its  consideration  will  be  left 
for  a  later  paper.  The  relation  of  the  contour  of  the  typical  curve 
obtained  on  electrical  stimulation  of  the  splanchnic  nerves  to  the  ad- 
renals, and  also  to  the  cardiac  mechanism,  has  been  dealt  with  by 
several  authors  (104),  (105),  (106),  (107).  A  further  analysis  of  this 
contour  is  also  postponed. 

Effect  of  repeated  occlusion  cm  intact  cats.  Elliott's  assumption  (75) 
that  adrenalin  is  consumed  under  conditions  of  stress  makes  it  con- 
ceivable that  the  rapid  repetition  of  so  radical  a  procedure  as  arterial 
occlusion  could  influence  the  amount  of  circulating  adrenalin.  Since 
the  relation  of  adrenalin  to  the  myo-neural  junction  has  been  experi- 
mentally demonstrated,  Professor  Pike  has  suggested  that,  physiolo- 
gically, it  may  be  associated  with  the  process  of  conduction  from  sym- 
pathetic nerve  fiber  to  smooth  muscle,  and  directly  or  indirectly  with 
the  processes  of  excitation  in  smooth  muscle.  The  work  of  Keith  Lucas 
would  suggest  such  a  possibility  (108).  Accordingly,  such  an  increase 
of  activity  of  sympathetic  nerve  and  smooth  muscle  as  accompanies 
cerebral  anemia  should  lead  to  a  more  rapid  consumption  of  adrenalin. 
This  conclusion  follows  from  Elliott's  hypothesis  of  the  consumption 
of  adrenalin.  The  procedure  of  repeated  occlusion  has  accordingly 
been  attempted  first  in  intact  animals  in  order  to  reach  a  control  condi- 
tion of  maximal  exhaustion  of  circulating  adrenalin,  and  then  in  animals 
in  which  the  adrenal  glands  had  been  permanently  ligated. 

The  great  resistance  of  the  animals  to  repeated  occlusion  has  been 
frequently  demonstrated  in  the  experimental  material  already  given. 
Numerous  other  evidences  of  the  relative  indefatigability  of  vasomotor 
responses  are  found  in  the  literature.  Notable  here  are  the  analogous 
experimental  conditions  in  the  work  of  Gushing  (99),  who  found  that 
the  process  of  raising  the  blood  pressure  by  increasing  the  intracranial 
tension,  and  thus  also  inducing  a  partial  anemia,  could  be  repeated 


CARDIOVASCULAR   CHANGES  DURING   CEREBRAL  ANEMIA  31 

indefinitely.  The  difficulty  of  inducing  fatigue  of  the  central  vasomotor 
cells  under  normal  conditions  has  been  discussed  in  various  connections 
by  W.  T.  Porter  (100),  (101). 

The  experiments  already  described  in  this  series  on  repetition  of 
occlusion  have  been  complicated  by  the  infliction  of  lesions  in  the 
splanchnic  system  so  that  the  actual  ability  of  the  animals  to  with- 
stand repeated  occlusions,  and  the  effect  of  this  procedure  on  the  anemic 
response,  was  not  clear.  Furthermore,  not  more  than  six  or  eight  suc- 
cessive occlusions  at  most  were  obtained.  Accordingly,  in  five  cats 
the  effects  of  repeated  occlusion  were  tested.  Occlusion  was  done  and 
when  the  final  spontaneous  fall  of  pressure  occurred,  the  clamps  were 
promptly  released  and  recovery  awaited.  The  corneal  reflex  was  used 
as  before  as  an  index  of  returned  bulbar  activity.  With  its  elicitation 
clamps  were  again  adjusted  on  the  head  arteries,  and  this  process 
repeated  several  times. 

If  the  occlusion  period  was  not  too  long  maintained  in  any  one  clos- 
ure, it  was  possible  to  repeat  the  procedure  practically  indefinitely. 
In  the  three  most  striking  experiments,  cats  45,  46  and  48,  the  experi- 
ments had  to  be  halted  arbitrarily  because  of  extraneous  reasons,  the 
time  consumed  being  too  long.  Cat  45  yielded  18  successive  occlu- 
sions (fig.  4);  cat  46,  13  successive  occlusions;  cat  49,  11  successive 
occlusions.  These  experiments  lasted  over  3  hours  in  addition  to  the 
time  necessary  for  the  preliminary  operative  manipulations  which 
always  consumed  over  half  an  hour.  Cat  46  was  intact,  cat  45  had 
suffered  double  vagotomy,  and  in  cat  48,  (fig.  5A)  both  stellate  ganglia 
had  been  removed.  No  marked  difference  in  the  behavior  of  these 
cats  under  the  test  could  be  noted.  In  fact,  the  cats  showed  a  remark- 
able constancy  in  behavior.  The  characteristic  occlusion  time — 2 
to  4  minutes — in  each  individual  was  retained  with  considerable  uni- 
formity throughout  each  series.  Furthermore,  the  time  needed  for 
recovery  of  the  bulbar  functions  after  release  of  the  arteries  was  almost 
uniform  for  each  cat  examined.  The  recovery  time  which,  on  the  whole, 
may  be  said  to  vary  directly  with  the  occlusion  time,  did  not  in  all 
cases  follow  this  relation.  Cat  46,  which  gave  a  constant  occlusion 
time  of  2  minutes  usually  showed  a  recovery  of  a  corneal  reflex 
within  7 .  minutes  subsequently.  Cat  45,  however,  (vagotomized) 
invariably  showed  a  20-minute  interval  between  occlusions.  In  this 
interval  a  well-marked  recovery  of  blood  pressure  was  noticeable  and, 
with  the  return  of  respiration,  blood  pressure  rose  at  least  from  60  to 
80  mm.  above  the  level  after  occlusion,  before  a  corneal  reflex  was 


32  CORA    SENNER   WINKIN 

obtained.  The  average  level  between  occlusions  was  relatively  high, 
pressure  seldom  falling  below  60  mm.  Hg. 

The  first  four  or  five  occlusions  obtained  differed  in  no  very  striking 
detail  from  control  occlusions.  The  main  change  from  the  type  of 
these  earlier  occlusions  appeared  gradually.  This  was  a  slight  delay 
in  the  appearance  of  the  first  rise  in  pressure  and  a  gradual  increase  in 
the  magnitude  of  this  first  effect.  The  fall  of  pressure  from  this  first 
level  also  became  more  pronounced;  pressure  dropped  to  increasingly 
lower  levels  at  this  time  on  successive  occlusions.  By  the  time  of  the 
seventh  or  ninth  occlusion  the  emphasis  on  this  first  part  of  the  curve 
became  so  well  marked  that  the  entire  response  appeared  more  as  two 
separate  curves  rather  than  one,  the  two  summits  in  the  tracing  being 
very  symmetrically  distributed  both  in  time  and  space.  The  fall  of 
pressure  following  the  initial  rise  was  so  great  in  some  of  the  animals 
as  to  approach  the  base  line  very  closely,  dropping  to  a  level  of  only 
10  to  20  mm.  Hg. 

The  characteristic  new  contour  of  the  rise,  once  established,  is  re- 
tained in  all  subsequent  tracings  in  the  same  animal  with  great  uni- 
formity (fig.  5B).  The  latter  part  of  the  series  of  occlusion  records 
accordingly  shows  this  new  type  of  anemic  rise.  The  marked  drop  in 
the  double  curve  is  quite  different  from  the  dip  due  to  vagus  action 
seen  in  the  ordinary  control  pressure  curve  of  anemia.  It  comes  much 
later  (fig.  4);  it  is  also  decidedly  more  abrupt  and  greater.  In  fact, 
it  seems  much  more  like  an  actual  collapse  of  blood  pressure.  It  appears 
uncomplicated  by  slowing  of  the  heart.  The  very  definite  time  rela- 
tions established  in  these  dissociated  curves  are  striking.  Indeed,  the 
supplementary  rise,  once  it  has  become  separated  from  the  initial  rise 
by  the  marked  temporary  collapse  of  blood  pressure,  is  recorded  at 
exactly  the  same  point  in  all  later  occlusions  obtained  in  a  given  animal. 
This  time  closely  approximates  half  of  the  occlusion  time  of  the  animal 
in  which  it  appears,  namely,  at  1  minute  in  cats  of  2-minute  occlusions, 
and  so  forth.  A  decrease  of  the  anemic  increment  was  obtained  in  the 
course  of  the  repetitions.  Rises  of  80  to  100  mm.  gradually  replaced 
the  original  increment  of  120  to  140  mm. 

One  further  observation  on  these  cats  is  worth  noting.  Post-mor- 
tem examination  showed  that  the  blood  of  these  animals  failed  to  clot 
readily.  It  frequently  flowed  freely  from  the  carotid  artery  when  the 
cannula  was  removed.  In  a  prolonged  dissection  in  one  animal,  the 
blood  flowed  freely  from  every  rupture  of  a  large  vessel,  even  as  late 
as  one  hour  after  death. 


CARDIOVASCULAR   CHANGES   DURING    CEREBRAL   ANEMIA 


33 


Effect  of  repeated  occlusions  in  cats  deprived  of  adrenal  glands.  The 
procedure  of  repeated  occlusion  in  the  same  animal  was  undertaken  in 
a  final  series  (six  cats)  in  which  both  adrenal  glands  were  ligated.  In 
each  of  these  animals  one  control  occlusion  was  made,  then  by  means 
of  dissection  through  the  latissimus  dorsi  (double  incision  from  the 
back)  the  adrenals  were  isolated  and  secured  by  ligatures.  No  signifi- 
cant fall  of  pressure  was  obtained  immediately  on  ligation  of  the  ad- 
renals, thus  confirming  the  observation  of  Hoskins  and  McClure  (102) 
and  Young  and  Lehman  (103).  Following  this,  the  procedure  was 


Fig.  5  A:  Control  curve  of  3  minute  occlusion.  Ligation  of  the  head  arteries 
in  the  intact  and  fresh  animal.  Initial  rise  is  followed  by  a  depression  level 
coming  cogether  with  a  slowing  of  the  heart.  High  level  of  pressure  maintained 
throughout  the  response. 

B.  Cat 48:  Repeated  cerebral  anemia;  stellate  ganglia  excised;  14th  successive 
occlusion.    Dissociation  of  two  peaks  very  well  marked.    Level  of  pressure 
between  occlusions  extremely  low  (20  mm.  Hg.  above  base  line). 

C.  Cat  53:  Repeated  cerebral  anemia;  adrenal  glands  ligated;  7th  successive 
occlusion,  obtained  just  before  collapse.     Drum  revolving  at  same  rate  as  above. 
Time  of  this  reaction,  2  minutes.     Control  reaction  in  this  animal,  when  fresh 
and  intact  had  occupied  3|  minutes.    Abruptness  of  initial  rise  and  final  fall 
characteristic  of  records  after  ligation  of  the  adrenals. 


THE   AMERICAN   JOURNAL   OF  PHYSIOLOGY,    VOL.    60,    NO.    1 


34  CORA    SENNER   WINKIN 

identical  to  that  in  intact  animals:  ether  was  reduced,  a  corneal  reflex 
elicited,  and  successive  occlusion  of  the  arteries  done  as  soon  as  recovery 
from  the  last  preceding  occlusion  had  occurred.  The  cats  differed 
somewhat  in  the  rapidity  with  which  the  effect  of  the  ligation  of  the 
adrenals  appeared  in  the  anemic  blood  pressure  curve.  In  two 
cats,  52  and  56,  the  first  occlusion  following  ligation  showed  little 
difference,  and  certainly  no  curtailment  when  compared  with  the 
control  curve.  In  cat  52  the  level  of  maximal  pressure  was  maintained 
2  full  minutes  longer  than  in  the  control.  However,  in  the  other  four 
cats,  the  curves  obtained  following  ligation  of  the  glands  immediately 
presented  a  marked  contrast  as  compared  with  the  normal  occlusion 
and  with  the  records  obtained  under  repeated  occlusion  in  the  control 
series  of  intact  animals.  The  characteristic  feature  of  this  change 
appeared  at  once  and  was  retained  until  failure  of  the  animal.  This 
was  an  absolute  halving  of  the  occlusion  time,  and  the  retention,  either 
of  a  reduced  double  curve,  or  of  a  single  vigorous  rise.  In  the  two  cats, 
52  and  56  already  referred  to,  this  same  reduction  appeared  somewhat 
later  in  the  record.  The  occlusion  time  was  not  halved  in  cat  52  until 
the  fifth  occlusion  following  ligation  of  the  glands;  in  cat  56,  not  until 
the  fourth  occlusion.  In  both  these  cats  there  also  remained  a  dis- 
tinct double  rise  in  the  pressure  curve,  which  was  not  observable  in 
the  curves  from  the  other  animals.  Autopsy  showed  no  difference 
in  the  completeness  of  the  ligation  in  these  two  animals. 

In  the  cats  in  which  the  adrenals  had  been  ligated  the  complete  in- 
ability to  restore  the  bulbar  functions  had  to  be  faced  in  all  cases  before 
nine  successive  occlusions  had  been  made.  There  were  no  exceptions 
to  this  early  complete  collapse  in  any  of  the  cats  observed.  Two  cats, 
54  and  52  already  mentioned,  gave  eight  successive  occlusions  after 
ligation  of  the  glands.  Cat  53  gave  seven;  (fig.  5  C)  cat  57,  five;  cat 
56,  otherwise  so  resistant  to  a  change  in  its  long  occlusion  periods  and 
retention  of  normal  contour,  succumbed  after  only  four  occlusions. 
Only  one  occlusion  was  obtained  from  cat  55.  Figured  in  hours  of 
survival  under  this  procedure,  this  meant  a  maximal  survival  of  2^ 
hours,  a  minimal  survival  of  15  minutes.  However,  only  two  cats  of 
the  series  failed  within  an  hour  of  the  ligation  of  the  glands  under  suc- 
cessive occlusions.  The  average  survival  time  was  1|  hours. 

Very  few  indications  of  the  approaching  collapse  appeared  in  the 
record,  the  only  index  being  perhaps  the  very  low  level  of  blood  pres- 
sure between  any  two  successive  occlusions.  This  low  level  was  estab- 
lished in  all  cases  immediately  after  the  spontaneous  fall  of  pressure 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  35 

closing  the  first  occlusion  that  followed  ligation  of  the  adrenals.  At 
this  time  pressure  fell  to  30  or  40  mm.  Hg. — a  level  20  to  30  mm.  lower 
than  in  the  intact  animals  at  a  corresponding  time.  In  spite  of  the 
subsequent  return  of  respiration  and  other  bulbar  activities,  the  pres- 
sure remained  uniformly  low.  A  return  of  the  corneal  reflex  was  ob- 
tained even  at  this  reduced  level.  The  level  of  blood  pressure  main- 
tained between  successive  occlusions  varied  somewhat.  On  comparing 
the  amount  of  recovery  of  blood  pressure  in  a  given  animal  after  occlu- 
sion, and  the  number  of  occlusions  obtainable,  it  was  found  that,  at 
least  in  the  extreme  cases,  a  direct  variation  could  be  noted.  The  two 
very  vigorous  animals  which  gave  eight  reactions  after  ligation  of  the 
glands,  cats  52  and  54,  showed  a  recovery  of  pressure  of  40  to  50  mm. 
during  the  period  following  release  of  the  head  arteries;  whereas  cats 
55  (one  occlusion)  and  57  (five  occlusions)  never  regained  more  than 
10  mm.  at  the  time  of  the  return  of  respiration.  Cats  53  (seven  occlu- 
sions) and  56  (four  occlusions)  occupied  a  rather  intermediate  position, 
never  showing  an  increase  of  more  than  20  mm.  pressure  during 
recovery  of  bulbar  function. 

No  change  in  the  time  needed  for  the  return  of  medullary  activity,  as 
determined  by  the  return  of  respiration  and  ocular  reflexes,  was  noted 
in  these  animals.  As  in  the  control  series  of  repeated  occlusion  in 
intact  animals,  this  was  not  different  after  ligation  of  the  adrenals  from 
that  obtained  in  the  fresh  animal.  Periods  of  recovery  of  from  10  to 
20  minutes  were  recorded,  being  fairly  constant  for  the  given  individual. 

No  significant  decrease  in  the  anemic  increment  was  observed,  in 
cats  53  (seven  occlusions)  and  57  (five  occlusions)  where  increments  of 
120  to  140  mm.  were  obtained  just  prior  to  failure.  These  were  oddly 
enough  the  smooth  curves  recorded  under  early  collapse.  A  much 
more  pronounced  decrease  in  the  anemic  increment  was  shown  in  the 
other  animals  in  which  more  occlusions  were  obtained;  in  cat  52, 
(eight  occlusions)  the  last  occlusion  recorded  showed  an  increment  of 
only  65  mm. 

The  contour  of  the  curves  obtained  is  of  considerable  interest.  Cats 
53  and  56  immediately  showed  a  single  rise  occupying  about  half  the 
original  occlusion  time  (fig.  6),  and  this  was  a  smooth  unbroken  curve. 
Though  the  reduction  in  time  was  just  as  manifest  in  all  the  other  cats, 
the  obliteration  of  the  double  nature  of  the  curve  was  not  so  clearly 
marked.  In  these  cats  the  characteristic  contour  of  the  anemic  rise 
as  seen  in  the  fresh  animal,  merged  gradually  into  the  smooth  curtailed 
curve  following  adrenal  ligation.  The  changes  most  evident  were  the 


36  CORA   SENNER    WINKIN 

greater  abruptness  of  the  initial  rise  while  the  depression  of  level  due 
to  vagus  activity  was  apt  to  be  increasingly  delayed  and  tended  to 
appear  on  the  crest^of  the  wave,  somewhat  similar  to  the  effect  described 
after  section  of  the  accelerators.  The  precipitous  fall  which  occurs  in 
these  animals  with  ligated  adrenals  just  about  half  as  late  as  in  intact 
cats  then  appears  as  soon  as  the  point  of  maximal  pressure  is  gained, 
namely,  immediately  after  cessation  of  the  vagus  depression. 


Fig.  6.  Cerebral  anemia  following  ligation  of  the  adrenals.  Cat.  53.  Arterial 
occlusion  immediately  following  tying  off  of  the  glands.  Occlusion  time,  1| 
minutes.  Time  of  control  occlusion  obtained  from  this  animal,  3  minutes. 

Effect  of  the  adrenal  glands  on  the  anemic  rise.  The  marked  shorten- 
ing of  the  anemic  response  eventually  obtained  in  all  the  animals  in 
which  the  adrenal  glands  had  been  ligated  seems  to  isolate  a  further 
factor  concerned  in  the  production  of  the  anemic  rise.  Apparently  the 
great  influence  which  the  splanchnic  system  is  able  to  exert  on  the  level 
of  blood  pressure  under  the  critical  conditions  of  anemia,  is  due  in  part 
to  the  adjuvant  activity  of  the  adrenal  glands.  These  experiments, 
therefore,  bear  on  the  discussion  of  the  emergency  relation  of  the  glands, 
since  apparently  some  involvement  of  the  glands  or  some  product  of 
their  activity  must  be  conceded  under  the  extreme  condition  of  cere- 
bral anemia.  Furthermore,  some  clue  as  to  the  nature  of  the  activity 
of  the  adrenals  is  given  by  inspection  of  the  curves  obtained. 

Loss  of  pressure.  There  has  been  noted  a  close  parallelism  between 
the  later  curves  obtained  from  all  animals  suffering  repeated  occlusion, 
whether  intact  or  deprived  of  adrenals.  A  failure  of  blood  pressure 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  37 

(temporary  or  permanent)  is  recorded  under  both  conditions  within 
half  the  time  normally  occupied  by  the  blood  vascular  response.  When 
the  animal  is  intact,  this  drop  of  pressure  occurs  in  the  seventh  or 
eighth  occlusion  and  in  all  subsequent  curves  of  a  given  series.  When 
the  adrenals  are  ligated,  it  may  be  established  immediately,  although 
this  is  not  necessarily  the  case.  Under  these  conditions  the  halving 
of  the  response  is  recorded  before  four  successive  occlusions  have  been 
inflicted  and  is  found  in  all  occlusions  which  follow  in  these  animals. 
This  precocious  loss  of  level  in  blood  pressure  can  therefore  be  obtained 
either  when  the  animal  has  been  exposed  to  rapidly  repeated  cerebral 
anemia,  or  when  the  activity  of  the  adrenal  glands  is  completely  abol- 
ished. Accordingly,  the  main  factor  in  the  production  of  this  early 
failure  of  pressure  seems  concerned  in  all  cases  with  the  availability 
in  the  blood  stream  of  some  product  of  adrenal  activity. 

Restoration  of  level  of  blood  pressure.  An  examination  of  the  supple- 
mentary rise  of  blood  pressure  in  the  repeatedly  occluded  but  intact 
cats  in  comparison  with  the  permanent  failure  of  pressure  at  half  the 
normal  occlusion  time  when  the  adrenals  are  ligated,  leads  to  a  consid- 
eration of  the  theories  of  emergency  function  of  the  adrenals.  This 
secondary  rise  is  most  probably  related  to  the  presence  of  functional 
adrenals. 

The  secondary  rise  was  interpreted  in  a  preliminary  report  of  these 
experiments  as  an  indication  of  an  increased  liberation  of  adrenalin 
from  the  glands,  and  the  constant  interval  prior  to  its  appearance,  as  a 
latent  period,  relatively  long,  of  adrenal  secretion.  The  argument  was 
advanced  that  these  experiments  offered  evidence  confirming  Cannon's 
position  on  the  increased  secretion  of  adrenalin  under  emergency  condi- 
tions. However,  in  view  of  the  presumable  consumption  of  the  pro- 
ducts of  adrenal  activity  during  cerebral  anemia  already  discussed,  the 
conception  of  the  emergency  liberation  of  adrenalin  must  be  somewhat 
modified.  The  further  discussion  of  any  of  the  current  hypotheses  of 
the  liberation  of  adrenalin  must  be  deferred  until  further  experimental 
evidence  has  been  accumulated.  Two  definite  statements,  however, 
appear  justified  by  the  facts.  In  the  first  place,  since  curves  of  per- 
fectly normal  contour  were  obtainable  in  two  animals  after  ligation  of 
the  adrenals,  an  increased  liberation  or  secretion  of  adrenalin,  one  or 
both,  is  not  necessary  for  the  carrying  out  of  the  typical  blood  vascular 
response  to  anemia  in  the  fresh  animal. 

That  these  results  were  due  to  experimental  error  can  hardly  be  pos- 
sible since  there  was  seen  in  these  animals  a  gradual  and  relatively  slow 


38  CORA   SENNEB   WINKIN 

transition  of  the  normal  curve  into  the  abbreviated  response  typical 
for  animals  with  ligated  adrenals.  Such  a  gradual  transition  is  also 
found  in  the  intact  repeatedly  occluded  animals.  In  the  second  place, 
from  the  premature  failure  of  the  vascular  response,  after  the  ligation 
of  the  adrenals,  particularly  in  contrast  to  the  secondary  rise  that  is 
seen  in  the  intact  repeatedly  occluded  animals,  the  conclusion  may  be 
drawn  that  some  product  of  adrenal  activity  must  be  available  to  make 
possible  the  continued  action  of  sympathetic  nerve  on  smooth  muscle 
for  any  length  of  time. 

Survival  after  adrenal  ligation.  In  all  the  work  reported  on  excision 
of  the  adrenal  glands,  sudden  death  has  never  been  noted.  However, 
when  all  adrenal  tissue  is  excised,  collapse  and  death  follow,  the  inter- 
val of  life  varying  in  different  animals.  The  earlier  work  on  cats  has 
been  reviewed  by  Hultgren  and  Anderson  (109),  who  particularly 
described  the  prelethal  stage.  Elliott  (73)  recorded  the  failure  of  blood 
pressure  in  addition  to  the  loss  of  the  pressor  reaction  in  the  moribund 
cat,  and  in  a  later  paper  he  has  summarized  a  series  of  tests  given  in 
these  conditions,  demonstrating  a  complete  collapse  of  vascular  tone. 
Gautrelet  and  Thomas,  (110)  later  Hoskins,  (111)  have  confirmed  the 
depression  of  the  sympathetic  system  on  final  collapse.  Elliott  records 
death  with  simultaneous  extirpation  under  ether  after  14  to  18  hours. 
Bazett  (112)  has  recently  succeeded  in  shortening  this  time  consider- 
ably by  decerebration,  urethane  anesthesia  and  sensory  stimulation. 
In  these  animals  the  fall  of  blood  pressure  occurred  within  a  few  hours 
after  the  operation.  Elliott  (98),  moreover,  finds  that  the  animal  sur- 
vives even  if  the  adrenal  tissue  is  separated  from  the  splanchnics.  He 
concludes  therefore  that,  whereas  the  increase  of  adrenalin  in  the  blood 
stream  under  splanchnic  stimulation  is  not  necessary  to  life,  the  animal 
depends  for  its  existence  on  the  continual  slow  secretion  of  adrenalin 
from  the  medullary  cells.  Elliott  argues  that  this  continual  slow 
secretion  is  independent  of  nervous  impulses.  Stewart  and  Rogoff 
(113),  (114),  however,  are  unable  to  demonstrate  any  appreciable 
adrenalin  output  under  these  conditions. 

It  seems  that  the  repetition  of  the  extreme  procedure  of  occlusion  is 
able  to  hasten  the  onset  of  complete  failure  most  surprisingly.  In  the 
extreme  conditions  of  these  experiments  Bazett's  (97)  already  curtailed 
time  of  survival  after  ligation  of  the  adrenals  is  thus  further  shortened 
by  6  or  8  hours.  The  only  demonstrable  factor  in  the  failure  under 
these  conditions  is  the  inability  of  the  sympathetic  nervous  mechanism 
to  maintain  the  normal  state  of  the  musculature  of  the  blood  vessels 


CARDIOVASCULAR   CHANGES   DURING    CEREBRAL   ANEMIA  39 

after  complete  exhaustion  of  the  reserve  of  adrenalin  in  the  blood. 
The  necessity  for  the  presence  of  adrenalin  or  of  some  other  product  of 
adrenal  activity  in  the  blood  for  the  maintenance  of  vasomotor  tone,  as 
asserted  by  Elliott,  seems  again  confirmed.  The  failure  of  blood  pres- 
sure alone  seems  able  to  carry  with  it  the  failure  of  all  the  other  functions. 

From  the  evidence,  the  relative  degree  of  constriction  of  the  vessel 
walls  seems,  to  a  considerable  extent,  a  function  of  the  amount  of  some 
adrenal  product  in  the  circulation.  The  loss  of  this  product  seems  to 
mean  complete  failure;  blood  pressure  stays  only  a  few  millimeters  above 
base  line  when  the  available  supply  is  low,  but  an  increased  liberation, 
or  possibly  even  a  redistribution,  may  give  any  degree  of  tonic  contrac- 
tion of  the  vascular  muscles,  reaching  to  maximum  constriction,  the 
entire  reaction  perhaps  depending  on  conditions  at  the  myo-neural 
junction. 

III.  RELATION  OF  THE  SPLANCHNIC  SYMPATHETIC  SYSTEM  TO  THE 
CENTRAL  NERVOUS  SYSTEM.  The  central  relations  of  the  sympathetic 
system  have  been  tenaciously  disputed,  and  cannot  be  entered  into  at 
length.  On  the  one  hand,  there  has  been  the  view  defending  its  rela- 
tive independence  from  the  cerebro-spinal  axis,  originally  advanced  by 
Bichat  (115),  and  supported  extensively  by  Volkmann  (116).  Goltz 
in  his  latest  work  with  Ewald  (117)  subscribed  to  this  view,  in  his  asser- 
tion that  the  sympathetic  peripheral  ganglia  could  maintain  normal 
vascular  tone,  and  mediate  reflexes  quite  independently  of  the  central 
nervous  system. 

However,  the  theory  that  the  nervous  outflow  is  essentially  dependent 
for  its  activity  on  cells  of  central,  and  particularly  bulbar  origin,  has 
always  enrolled  some  powerful  supporters.  Two  of  Goltz's  contempo- 
raries, Eckhard  (118)  and  Mayer  (119)  have  defended  this  conception. 
Recently  Gaskell  (120)  and  Sherrington  (121)  and  still  later  Ranson, 
(122),  also  endorsed  it. 

Two  points  in  the  evidence  on  cerebral  anemia  will  briefly  cover  the 
relation  of  the  medullary  cells  to  the  peripheral  response.  First,  the 
comparison  of  the  splanchnic  response  with  the  other  peripheral  re- 
sponses, and  particularly  the  skeletal  responses  as  controlled  by  the 
medullary  or  higher  cells,  under  the  different  functional  conditions  of 
the  nervous  levels  in  these  experiments;  second,  the  behavior  of  the  blood 
pressure  responses  under  recovery  from  various  spinal  lesions. 

Comparison  of  splanchnic  response  with  other  peripheral  responses. 
The  following  table  gives  the  various  stages  which  can  be  distinctly 
separated  when  different  functional  levels  control  the  animal's  reac- 


40  CORA   SENNER   WINKIN 

tion.  The  rough  average  of  the  level  of  blood  pressure  maintained  is 
given  for  each  period.  The  exact  correspondence  of  the  involvement 
of  the  splanchnic  system  and  the  degree  of  functional  activity  within 
the  medullary  centers  is  indeed  striking,  especially  in  view  of  the  po- 
tency of  the  splanchnic  system  in  maintaining  blood  pressure.  It 
appears  from  this  tabulation  that  the  splanchnic  system  behaves  ex- 
actly as  do  the  respiratory,  skeletal  and  ocular  responses.  When  the 
skeletal  responses  dependent  on  the  higher  levels  are  in  abeyance,  the 
vasomotor  responses  of  the  splanchnic  system  are  also  absent.  At 
this  time,  moreover,  that  is,  during  the  depression  between  occlusions, 
the  heart  rate  shows  no  appreciable  change.  The  level  of  blood  pres- 
sure maintained  is  that  shown  by  Gouty  (16),  Mayer  (14),  Pike  (26) 
and  Langley  (27)  to  be  that  held  as  long  as  the  spinal  cord  itself  remains 
intact.  Additional  evidence  that  the  depression  of  functional  activity 
is  due  to  a  complete  interruption  of  conduction  in  the  spinal  cord,  and 
not  to  so-called  spinal  shock,  is  brought  out  by  the  behavior  of  the 
animal  in  passing  through  these  various  stages.  The  bearing  of  the 
validity  of  the  shock  hypothesis  for  any  conception  of  the  functional 
organization  of  the  nervous  system  has  been  discussed  by  Pike  (123).  A 
.shorter  statement  of  this  relation  is  found  in  Yates's  paper  (36) . 

Comparison  of  somatic  and  ocular  responses  with  vascular  responses 

Control  of  the  animal's  responses  by  various  nervous  levels  Average  level  of  blood  pressure 

1.  Normal  intact  animal:  responds  as  a  whole,  pupils 

narrow,  corneal  reflex,  respiration  normal 120  mm. 

2.  Head     subjected     to     anemia:  struggles — responses 

under  control  of  stimulated  area  (head)  skeletal 
'  convulsions,  respiratory  spasms,  corneal  reflex  lost.        180-200  mm. 

3.  Head  functionally  dead, — animal  spinal:— responses 

under  control  of  spinal  cord  only  no  corneal  reflex, 
pupils  widely  dilated.  No  spontaneous  respira- 
tion. No  skeletal  reflexes  elicitable 50-70  mm. 

4.  Recovery  of  head  centers :  gradual  return  of  responses 

controlled  by  head  area,  pupils  narrowing — no  cor- 
neal reflex — spontaneous  respiration  returns  after 
pressure  has  risen  somewhat,  but  still  sporadic. 
Skeletal  reflexes  elicitable  in  part 70-90  mm. 

5.  Recovery  completed;  animal  responds  as  a  whole. 

Pupils  narrow,  corneal  reflex,  respiration  reestab- 
lished; functions  coordinately,  skeletal  reflexes 
present 120  mm. 

When  a  significant  lesion  in  the  splanchnic  system  has  been  inflicted 
by  the  section  of  these  nerves  just  before  entrance  into  the  coeliac 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  41 

ganglion  and  the  cerebral  circulation  shut  off,  no  anemic  increment  is 
obtainable.  However,  all  other  evidences  of  bulbar  activity  are  present. 
A  vigorous  corneal  reflex  is  obtained  prior  to  occlusion,  and  when  the 
clamps  are  adjusted,  even  though  the  level  of  pressure  may  remain  more 
undisturbed  than  that  obtained  under  many  minor  manipulations,  the 
other  symptoms  of  the  asphyxial  response  are  shown  in  full  vigor. 
There  are  marked  respiratory  spasms,  skeletal  convulsions,  changes  in 
the  pupils,  etc. 

In  marked  contrast  to  such  a  picture  are  the  effects  when,  from  some 
physiological  disturbance,  the  medulla  itself  is  thrown  out  of  activity. 
Here  the  effects  of  the  interruption  of  functional  continuity  are  opposed 
to  the  effect  of  anatomical  separation.  Such  a  condition  is  present 
while  the  animal  is  still  profoundly  under  the  effect  of  an  occlusion  that 
has  just  been  done,  or  even  during  recovery  from  occlusion,  when  the 
functions  of  the  brain  stem  are  not  yet  fully  established.  If,  under  such 
conditions,  the  animal  is  subjected  to  a  renewed  occlusion,  no  response 
at  all  can  be  aroused.  Generalized  asphyxia,  inflicted  by  clamping  the 
trachea  and  thus  acting  directly  at  the  periphery  is,  in  this  condition, 
also  impotent  to  produce  any  effect.  Under  this  general  depression 
there  are  no  skeletal  convulsions,  no  respiratory  gasps,  and  pressure 
changes  are  extremely  slight,  5  or  10  mm.  The  heart  just  quietly  runs 
down.  The  condition  of  the  eyes  remains  unchanged  throughout. 

All  the  evidence  of  these  experiments  therefore  would  argue  not  only 
for  a  normal  release  of  the  rise  of  blood  pressure  through  the  sympathetic 
outflow,  but  also  for  a  complete  dependence  of  the  activation  of  the 
response  on  the  integrity  of  the  brain  stem,  and  the  maintenance  of  the 
conditions  of  conductivity  within  it.  The  response  transmitted  by  the 
sympathetic  system  is  functionally  exactly  on  a  par  with  all  the  other 
physiological  responses.  When  respiratory  movements,  eye  move- 
ments and  skeletal  reflexes  are  obtainable,  the  changes  of  blood  pressure 
can  also  be  elicited. 

The  anatomical  relations  of  the  splanchnic  outflow  in  its  bearing  on 
recovery  after  section  of  the  spinal  cord.  The  complete  dependence  on 
the  brain  rather  than  on  the  spinal  cord  is  well  illustrated  by  experi- 
ments on  recovery  of  blood  pressure  from  high  section  of  the  spinal 
cord.  Goltz,  (17),  (18)  and  later  Goltz  and  Ewald  (117)  sectioned  the 
cord  of  dogs  in  the  midthoracic  region  and  found  normal  blood  pres- 
sure responses  to  subsist.  These  were  attributed  entirely  to  the  con- 
trolling influence  of  the  cord  over  the  sympathetic  system.  These 
experiments  have  been  repeated  by  later  investigators,  notably  Sher- 


42  CORA   SENNER   WINKIN 

rington  (121),  (124).  In  view  of  the  very  high  level  of  the  cord  in  which 
a  lesion  must  fall  before  it  can  definitely  intercept  the  connections 
between  the  medulla  and  the  splanchnic  effectors,  there  is  a  possibility 
that -the  agency  concerned  in  this  recovery  is  none  other  than  the 
splanchnic  constrictors  still  in  functional  continuity  with  the  brain  stem. 

Four  early  experiments  were  carried  out  with  Doctor  Pike's  coopera- 
tion in  which  a  transection  in  the  upper  levels  of  the  spinal  cord  was 
done  aseptically,  the  animal  allowed  to  recover'  and  then  the  anemic 
response  tested.  In  two  cats  the  transection  was  done  at  the  level  of 
the  2nd  thoracic.  One  animal  died  within  24  hours  before  the  blood 
pressure  could  be  tested;  the  other  lived  5  days  and  was  then  subjected 
to  the  test  of  occlusion.  Blood  pressure,  however,  was  very  low,  the 
bulbar  responses  failed  immediately  and  no  rise  was  elicitable.  Cat 
63,  however,  in  which  section  at  the  3rd  thoracic  was  made,  recovered 
fully  and  when  tested  a  week  later  showed  a  level  of  blood  pressure  of 
120  mm.  and  an  anemic  increment  of  50  mm.  in  the  first  occlusion. 
Cat  64  with  a  section  at  the  6th  thoracic  was  tested  2  days  later.  Con- 
trol level  of  blood  pressure  was  80  mm.  The  anemic  increment  of  the 
first  occlusion  was  45  mm. 

This  problem  was  subsequently  taken  up  by  Miss  Yates  under  Doc- 
tor Pike's  direction,  and  has  been  reported  on  in  detail  in  an  earlier 
issue  of  this  Journal.  Miss  Yates  (36)  found  that  when  one  or  two 
segments  of  the  thoracic  region  only  are  left  intact  there  is  a  recovery 
of  blood  pressure  to  an  adequate  level,  and  vigorous  anemic  or  asphyx- 
ial  response  is  readily  elicitable.  This  recovery  is  attributable  to  those 
medullary  cells  still  in  connection  with  the  peripheral  splanchnic 
neurones. 

It  was  on  the  evidence  of  Goltz's  experiments  that  Langley  applied 
the  name  "autonomic"  to  those  peripheral  mechanisms  supplied  by 
ganglionic  connection  outside  the  nervous  system  which  he  thought 
could  function  independently  of  the  brain.  The  physiological  evidence 
that  is  now  accumulating  would  gravely  discredit  this  autonomy,  and 
would  tend  to  place  the  sympathetic  responses  in  the  same  category  as 
all  others.  This  is  of  particular  importance  in  connection  with  the 
late  appearance  of  the  adrenal  effect  in  cerebral  occlusion,  even  after 
the  reflexes  are  no  longer  elicitable.  However  late  its  appearance,  and 
however  independent  of  any  parallel  nervous  activity,  this  effect  cer- 
tainly cannot  be  aroused  unless  the  splanchnic  fibers  themselves  have 
been  previously  stimulated.  When  the  splanchnic  fibers  are  no  longer 
excitable  because  of  an  anatomical  lesion  the  adrenal  effect  never 
appears.' 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  43 

This  relationship  is  of  particular  interest  with  respect  to  the  appear- 
ance of  Traube-Hering  waves.  These  have  been  noticed  by  all  ob- 
servers in  the  downward  course  of  the  final  fall  of  blood  pressure  in  the 
anemic  response.  Whether  nervous  centers  are  no  longer  excitable  to 
sensory  stimulation  and  whether  or  not  the  output  of  adrenalin  is  a 
factor  concerned,  remains  to  be  tested.  It  must,  however,  be  borne  in 
mind  that  such  a  condition  as  this  where  Traube-Hering  waves  have  been 
elicited,  is  preceded  by  an  intense  activity  of  the  splanchnic  outflow 
as  stimulated  by  the  medullary  cells. 

In  the  disturbance  of  the  internal  medium  which  the  excessive  con- 
centration of  carbon  dioxide  in  the  occluded  cerebral  vessels  brings 
with  it,  the  increased  rate  of  flow  is  carried  out  and  maintained  by  the 
vascular  musculature,  and  some  product  of  adrenal  activity  probably 
makes  possible  the  maintenance  of  the  increased  impetus  given  the 
blood  flow  through  such  a  prolonged  period  of  time.  However,  it  is 
only  by  virtue  of  the  neurones  within  the  central  nervous  system  that 
the  response  is  initiated,  that  it  is  regulated  by  changes  in  the  cardiac 
musculature,  and  finally  that  the  response  is  carried  out  as  an  integrated 
whole.  The  retention  of  a  constant  tension  of  carbon  dioxide  in  the 
blood  by  means  of  an  adaptive  blood  vascular  reaction,  is  therefore 
mediated  in  the  mammal  through  its  higher  central  nervous  organiza- 
tion, particularly  the  cells  within  the  medulla  oblongata. 

To  Prof.  F.  H.  Pike  the  writer  is  greatly  indebted  for  suggestions, 
advice  and  criticism,  extended  throughout  the  research. 

CONCLUSIONS 

1.  The  nerves  of  the  heart  are  not  essential  either  for  the  activation 
or  for  the  persistence  of  the  characteristic  pressor  phenomena  of  the 
anemic  rise. 

2.  In  the  early  stages  of  cerebral  occlusion  the  cardiac  innervation 
functions  as  a  check  on  the  rapid  rise  of  blood  pressure.     In  this  modera- 
ting action,  accelerators  as  well  as  vagi  are  involved,  since  on  excision 
of  the  stellate  ganglia,  the  vagi  alone  are  unable  to  prevent  an  abrupt 
and  steep  rise  of  pressure. 

3.  The  activation  and  maintenance  of  the  vascular  response  under 
cerebral  occlusion  is  controlled  essentially  by  the  splanchnic  nerves. 

4.  Differential  section  in  various  regions  of  the  splanchnic  outflow 
influences  the  level  of  the  arterial  blood  pressure.    The  extent  to  which 
the  pressure  falls  on  section  is  an  approximate  index  of  the  degree  to 
which  the  anemic  rise  will  be  compromised  by  the  lesion. 


44  CORA   SENNEE  WINKIN 

5.  It  is  impossible  to  influence  the  vascular  response  to  anemia  by 
indiscriminate  sections  within  the  splanchnic  outflow.     In  order  defi- 
nitely to  abolish  the  response,  it  is  necessary  to  section  either  suffi- 
ciently far  out  in  the  periphery,  or  sufficiently  high  up  in  the  spinal  cord 
to  interrupt  completely  the  continuity  between  the  medulla  and  the 
coeliac  ganglion. 

6.  The  level  at  which  the  fibers  of  the  splanchnic  system  leave  the 
spinal  cord  varies  in  different  individuals.     The  greatest  number  of 
fibers  leave  the  cord  in  the  lower  thoracic,  especially  in  the  region  of  the 
6th  to  8th  thoracic.     However,   constrictor  fibers  to  the  splanchnic 
nerves  leave  the  cord  throughout  the  higher  levels  of  the  thoracic  cord. 
In  certain  individuals,  fibers  leaving  as  high  as  the  2nd  and  3rd  thor- 
acic will  maintain  an  appreciable  level  of  blood  pressure  and  activate 
a  significant  anemic  response. 

7.  Cerebral  occlusion,  carried  out  in  repeated  succession,  is  borne 
indefinitely  (as  many  as  18  times)  in  intact  animals.     The  occlusion 
time  is  in  no  way  curtailed  and  the  anemic  increment  of  blood  pressure 
only  slightly  diminished. 

8.  The  curve  of  the  anemic  rise  under  repeated  cerebral  occlusion 
becomes  dissociated  into  two  distinct  parts  after  eight  or  ten  successive 
occlusions  have  been  inflicted. 

9.  The  long-continued  maintenance  of  blood  pressure  at  an  extremely 
high  level,  characteristic  of  the  anemic  rise,  is  no  longer  possible  after 
any  gross  interference  with  the  supply  of   some   product  of   adrenal 
activity. 

10.  An  increased  liberation  of  adrenalin  under  extreme  splanchnic 
stimulation  cannot  be  demonstrated  as  necessary  for  the  characteristic 
contour  of  the  anemic  rise.     This  appears  dependent  on  the  amount  of 
circulating  adrenalin. 

11.  An  increased  availability  of  some  product  of  adrenal  activity 
appears  demonstrable  in  intact  animals  under  extreme  splanchnic  stimu- 
lation, after  eight  or  ten  successive  occlusions  have  been  inflicted. 

12.  Survival  after  ligation  of  the  adrenal  glands  may  be  reduced  to 
1  or  2  hours,  when  the  animal  is  subjected  to  successive  repeated  cere- 
bral occlusions.    A  complete  failure  of  vasomotor  tone  seems  demon- 
strable in  these  animals. 

13.  The  response  of  the  splanchnic  nerves  is  dependent  for  its  release 
on  conditions  of  functional  activity  within  the  brain  stem. 

14.  The  vasomotor  responses  initiated  by  the  splanchnic  nerves  of 
the  sympathetic  nervous  system  are  comparable  with  skeletal  responses 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  45 

dependent  on  the  higher  nervous  levels,  in  respect  to  their  complete 
dependence  on  these  levels  of  the  central  nervous  axis. 

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(54)  VON  ANREP:  Jour.  Physiol.,  1912,  xlv,  307. 

(55)  CATHCART  AND  CLARK:  Journ.  Physiol.,  1914,  xlix,  301. 

(56)  NAWALICHIN:  Centrlbl.  Med.  Wis.,  1870,  483. 

(57)  Cited  by  TIGERSTEDT:  Ergebn.  d.  Physiol.,  1906,  vi,  265. 

(58)  ERLANGER:  Proc.  Amer.  Physiol.  Soc.,  This  Journal,  1904,  x,  p.  xiv. 

(59)  HILL:  Schaefer's  Textbook,  1900,  57. 

(60)  WICKWIRE-.    This  Journal,  1920,  liii,  355. 

(61)  Mosso:  L'Impartialle  xii,  1872. 

(62)  HUNT:  Journ.  Exper.  Med.,  1897,  ii,  2. 

(63)  STEWART  -AND  ROGOFF:  This  Journal,  1920,  lii,  304. 

(64)  LANGLEY:  Schafer's  Textbook,   1900,  462. 

(65)  RANSON  AND  BiLLiNGSLEY:  Journ.  Comp.  Neurol.,  1918,  xxix,  405. 

(66)  SHERRINGTON:  Mammalian  physiology,   1919,  Oxford,  41. 

(67)  BAYLISS:  Journ.  Physio].,  1893,  xiv,  303. 

(68)  OLIVER  AND  SCHAFER:  Journ.  Physiol.,  1895,  xviii,  230. 

(69)  BIEDL:  Arch.  f.  d.  gesammt.  Physioi:,  1897,  Ixvii,  433. 

(70)  DREYER:  This  Journal,  1897,  ii,  203. 

(71)  LEWANDOWSKY:  Arch.  f.  Anat.  u.  Physiol.,  1899,  360. 

(72)  LANGLEY:  Journ.  Physiol.,  1907,  xxvii,  237. 

(73)  ELLIOTT:  Journ.  Physiol.,  1905,  xxxii,  401. 

(74)  ELLIOTT:  Journ.  Physiol.,  1913,  xivi,  285. 

(75)  ELLIOTT:  Journ.  Physiol.,  1912,  xliv,  375. 

(76)  CANNON  AND  DE  LA  PAZ:  This  Journal,  1911,  xxviii,  64. 

(77)  HOSKINS:  Journ.  Pharm.  Exper.  Therap.,  1911,  iii,  93. 

(78)  FOLIN,  GANNON  AND  DENIS:  Journ.  Biol.  Chem.,  1913,  xiii,  477. 

(79)  STEWART:  Journ.  Exper.  Med.,  1911,  xiv,  377. 

(80)  STEWART  AND  ROGOFF:  Journ.  Pharm.  Exper.  Therap.,  1916,  viii,  479. 

(81)  STEWART  AND  ROGOFF:  Journ.  Pharm.  Exper.  Therap.,  1917,  ix,  393. 

(82)  ROGOFF:  Journ.  Lab.  Clin.  Med.,  1918,  iii,  2. 

(83)  CANNON  AND  HOSKINS:  This  Journal,  1911,  xxix,  274. 

(84)  CANNON:  This  Journal,  1914,  xxxiii,  356. 

(85)  CANNON:  Bodily  changes  in  pain,  hunger,  fear  and  rage,  New  York,  1915. 

(86)  STEWART  AND  ROGOFF:  Journ.  Pharm.  Exper.  Therap.,  1917,  x,  49. 

(87)  STEWART  AND  ROGOFF:  This  Journal,  1917,  xliv,  149. 

(88)  STEWART  AND  ROGOFF:  This  Journal,  1918,  xlvi,  93. 


CARDIOVASCULAR   CHANGES   DURING   CEREBRAL   ANEMIA  47 

(89)  BCJRTON-OPITZ:  Quart.  Journ.  Exper.  Physiol.,  1912,  v,  82. 

(90)  BURTON-OPITZ :  Quart.  Journ.  Exper.  Physiol.,  1912,  v,  309. 

(91)  STEWART  AND  ROGOFF:  Journ.  Exper.  Med.,  1916,  xxiv,  709. 

(92)  GLEY  AND  QUINQUAUD:  Journ.  Physiol.  et  Path,  gen.,  1918,  xvii,  807. 

(93)  TSCHEBOKSAROFF:  Arch.  f.  d.  gesammt.  Physiol.,  1911,  cxxxvii,  59. 

(94)  HOSKINS  AND  MCCLURE:  Arch.  Int.  Med.,  1912,  x,  343. 

(95)  CYBULSKI:  Wien.  Med.  Wochenschr.,  1896,  xlvi,  6. 

(96)  GLEY  AND  QUINQUAUD:  Compt.  rend.  soc.  biol.,  1917. 

(97)  CZUBALSKI:  Gentrbl.  Physiol.,  1913,  xxvii,  580. 

(98)  ELLIOTT:  Journ.  Physiol.,  1914,  xlix,  38. 

(99)  GUSHING:  Grenzgebiet  Med.  u.  Chir.— Physiol.  Anat.  Beqb.,  1902. 

(100)  PORTER,  MARKS  AND  SWIFT:  This  Journal,  1908,  xx,  40. 

(101)  PORTER:  Harvey  Lectures,  1906-7. 

(102)  HOSKINS  AND  MCCLURE:  This  Journal,  1912,  xxx,  192. 

(103)  YOUNG  AND  LEHMAN:  Journ.  Physiol.,  1908,  xxxvii,  p.  liv. 

(104)  BURTON-OPITZ  AND  EDWARDS  :  This  Journal,  1916,  xli,  91. 

(105)  JOHANNSEN:  Arch.  Anat.  u.  Physiol.,  1891,  103. 

(106)  LEHNDORFF:  Arch.  Anat.  u.  physiol.,  1908,  362. 

(107)  PEARLMAN  AND  VINCENT:  Endocrinology,  1919,  iii,  121. 

(108)  LUCAS:  Conduction  of  the  nervous  impulse,  London,  1920,  70. 

(109)  HULTGREN  AND  ANDERSEN:  Skand.  Arch.  Physiol.,  1899,  ix,  73. 

(110)  GAUTRELET  AND  THOMAS  :  Compt.  rend.  soc.  de.  biol.,  1909,  388. 

(111)  HOSKINS:  This  Journal,  1915,  xxxvi,  423. 

(112)  BAZETT:  Journ.  Physiol.,  1920,  liii,  320. 

(113)  STEWART  AND  ROGOFF:  Journ.  Pharm.  Exper.  Therap.,  1917,  xi,  1. 

(114)  STEWART  AND  ROGOFF:  This  Journal,  1919,  xlviii,  397. 

(115)  BICHAT:  Anatomic  Generale,  1830,  i,  285. 

(116)  VOLKMANN:  Wagner's  Handworterbuch,   1879. 

(117)  GOLTZ  AND  EWALD:  Arch.  f.  d.  gesammt.  Physiol.,  1896,  Ixiii,  362. 

(118)  ECKHARD:  Hermann's  Handb.,  1879,  ii,  2. 

(119)  MAYER:  Hermann's  Handb.,  1879,  ii,  275. 

(120)  GASKELL:  Involuntary  nervous  system,  London,  1916. 

(121)  SHERRINGTON:  The  integrative  action  of  the  nervous  system,  New  Haven, 

1906,  243,  308. 

(122)  RANSOM:  Nervous  system,  Philadelphia,  1921. 

(123)  PIKE:  Journ.  Comp.  Neurol.,  1918,  xxix,  485. 

(124)  SHERRINGTON:  Proc.  Roy.  Soo.,  Ixvi. 


CURRICULUM  VITAE 

Cora  Senner  Winkin  was  born  in  the  city  of  New  York,  March  23, 1893. 
She  was  prepared  for  college  at  the  Ethical  Culture  High  School,  from 
which  she  graduated  in  1911.  She  received  the  degree  of  A.B.  from 
Barnard  College  in  1916,  and  was  admitted  to  the  graduate  school  of 
Columbia  University  in  the  same. year. 


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DEC  17  1930 

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PAT.  JAN  21,  1908 


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